Cysteine protease inhibitors

ABSTRACT

Compounds of the formula I 
     
       
         
         
             
             
         
       
     
     wherein 
     R 1a  is H; and R 1b  is C 1 -C 6  alkyl, Carbocyclyl or Het; or 
     R 1a  and R 1b  together define a saturated cyclic amine with 3-6 ring atoms; 
     R 2a  and R 2b  are H, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy; or 
     R 2a  and R 2b  together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl; 
     R 3  is a branched C 5 -C 10 alkyl chain, C 2 -C 4 haloalkyl or C 3 -C 7 cycloalkylmethyl, 
     R 4  is Het, Carbocyclyl, 
     optionally substituted as defined in the specification and pharmaceutically acceptable salts, 
     hydrates and N-oxides thereof; are inhibitors of cathepsin S and have utility in the treatment of psoriasis, autoimmune disorders and other disorders such as asthma, arteriosclerosis, COPD and chronic pain

TECHNICAL FIELD

This invention relates to inhibitors of cathepsin S, and their use inmethods of treatment for disorders involving cathepsin S such asautoimmune disorders, allergy and chronic pain conditions.

BACKGROUND TO THE INVENTION

The papain superfamily of cysteine proteases are widely distributed indiverse species including mammals, invertebrates, protozoa, plants andbacteria. A number of mammalian cathepsin enzymes, including cathepsinsB, F, H, K, L, O, S, and W, have been ascribed to this superfamily, andinappropriate regulation of their activity has been implicated in anumber of metabolic disorders including arthritis, muscular dystrophy,inflammation, glomerulonephritis and tumour invasion. Pathogeniccathepsin like enzymes include the bacterial gingipains, the malarialfalcipains I, II, III et seq. and cysteine proteases from Pneumocystiscarinii, Trypanosoma cruzei and brucei, Crithidia fusiculata,Schistosoma spp.

In WO 97/40066, the use of inhibitors against Cathepsin S is described.The inhibition of this enzyme is suggested to prevent or treat diseasecaused by protease activity. Cathepsin S is a highly active cysteineprotease belonging to the papain superfamily. Its primary structure is57%, 41% and 45% homologous with the human cathepsin L and H, and theplant cysteine protease papain respectively, although only 31%homologous with cathepsin B. It is found mainly in B cells, dendriticcells and macrophages and this limited occurrence suggests the potentialinvolvement of this enzyme in the pathogenesis of degenerative disease.Moreover, it has been found that destruction of Ii by proteolysis isrequired for MHC class II molecules to bind antigenic peptides, and fortransport of the resulting complex to the cell surface. Furthermore, ithas been found that Cathepsin S is essential in B cells for effective Iiproteolysis necessary to render class II molecules competent for bindingpeptides. Therefore, the inhibition of this enzyme may be useful inmodulating class II-restricted immune response (WO 97/40066). Otherdisorders in which cathepsin S is implicated are asthma, chronicobstructive pulmonary disease, endometriosis and chronic pain.

BRIEF DESCRIPTION OF THE INVENTION

According to a first aspect of the invention there is provided acompound of the formula I:

wherein

-   R^(1a) is H; and-   R^(1b) is C₁-C₆ alkyl, optionally substituted with 1-3 substituents    independently selected from: halo, hydroxy, cyano, azido,    C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy, C₁-C₄alkoxycarbonyl,    C₁-C₄alkylcarbonyl, amine, C₁-C₄alkylamine, C₁-C₄-dialkylamine,    C₁-C₄alkylsulfonyl, C₁-C₄alkylsulfonylamino, aminocarbonyl,    aminosulphonyl, Carbocyclyl and Het; or-   R^(1b) is Carbocyclyl or Het; or-   R^(1a) and R^(1b) together with the N atom to which they are    attached define a saturated cyclic amine with 3-6 ring atoms;-   wherein the Carbocyclyl, Het or cyclic amine is optionally    substituted with 1-3 substituents independently selected from halo,    hydroxy, cyano, azido, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,    C₁-C₄haloalkoxy, C₁-C₄alkoxycarbonyl, C₁-C₄alkylcarbonyl, amino,    C₁-C₄alkylamino, C₁-C₄dialkylamino, C₁-C₄alkylsulfonyl,    C₁-C₄alkylsulfonylamino, aminocarbonyl, aminosulphonyl,    RxOC(═O)-C₀-C₂alkylenyl (where Rx is H, C₁-C₄alkyl or    C₁-C₄haloalkyl), phenyl, benzyl or C₃-C₆cycloalkyl-C₀-C₂alkylenyl;-   wherein the phenyl, benzyl or cycloalkyl moiety is optionally    substituted with 1-3 substituents independently selected from halo,    C₁-C₄alkyl, C₁-C₄haloalkyl or C₁-C₄alkoxy;-   R^(2a) and R^(2b) are independently selected from H, halo,    C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy; or-   R^(2a) and R^(2b) together with the carbon atom to which they are    attached form a C₃-C₆cycloalkyl;-   R³ is a C₅-C₁₀alkyl, optionally substituted with 1-3 substituents    independently selected from halo, C₁-C₄haloalkyl, C₁-C₄alkoxy,    C₁-C₄haloalkoxy; or-   R³ is a C₂-C₄alkyl chain with at least 2 chloro or 3 fluoro    substituents; or-   R³ is C₃-C₇cycloalkylmethyl, optionally substituted with 1-3    substituents selected from C₁-C₄alkyl, halo, C₁-C₄haloalkyl,    C₁-C₄alkoxy or C₁-C₄haloalkoxy;-   R⁴ is Het or Carbocyclyl, either of which is optionally substituted    with 1-3 substituents independently selected from:    -   halo, azido, cyano, hydroxy, oxo, C₁-C₄alkyl, C₁-C₄haloalkyl,        C₁-C₄alkoxy, C₁-C₄haloalkoxy, C₁-C₄alkoxycarbonyl,        C₁-C₄alkylcarbonyl, C₁-C₄alkylsulfonyl, C₁-C₄alkylsulfonylamino,        aminosulphonyl, —NRkRl, —C(═O)NRkRl, —NRkC(═O)Rl, NRkC(═O)ORl,        —NRk(C═O)NRkRl, wherein oxo as substituent may be present only        where valence so permits,    -   where Rk and Rl are independently H, C₁-C₄ alkyl, or one is H        and the other is —C(═O)C₁-C₄alkyl;    -   and/or wherein in the Het or Carbocyclyl group is optionally        substituted with a group of the formula —X—R5;        -   wherein X is C₁-C₄alkylene or a 1-4 membered linkage            comprising 0-3 methylene groups disposed adjacent to, or on            either side of a CH(CH₃), C(CH₃)₂, CF₂, ethene, ethyne,            C₀-C₄alkylamino, C₀-C₄alkylamido, sulphonamido,            aminosulphonyl, ester, ether, urea or carbamate function; R⁵            is H, C₁-C₄alkyl or a monocyclic ring selected from            C₃-C₆cycloalkyl, C₃-C₆cycloalkenyl, phenyl, pyrrolidinyl,            piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,            indolinyl, pyranyl, tetrahydropyranyl,            tetrahydrothiopyranyl, thiopyranyl, furanyl,            tetrahydrofuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,            thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl,            pyridazinyl, tetrazolyl, pyrazolyl, indolyl, the C₁-C₄alkyl            or monocyclic ring being optionally substituted with one to            three substituents selected from:            -   halo, azido, cyano, hydroxy, C₁-C₄alkyl, C₁-C₄haloalkyl,                C₁-C₄alkoxy, C₁-C₄haloalkoxy, C₁-C₄alkoxycarbonyl,                C₁-C₄alkylcarbonyl, amino, C₁-C₄alkylamino,                C₁-C₄-dialkylamino, C₁-C₄alkylsulfonyl,                C₁-C₄alkylsulfonylamino, aminocarbonyl, aminosulphonyl;

Het is a stable, monocyclic or bicyclic, saturated, partially saturatedor aromatic ring system, containing 1-4 hetero atoms independentlyselected from O, S and N, and each ring having 5 or 6 ring atoms;

Carbocyclyl is C₃-C₆cycloalkyl, C₅-C₆cycloalkenyl or phenyl;

or a pharmaceutically acceptable salt, hydrate or N-oxide thereof.

In some embodiments, R^(1a) is H and R^(1b) is C₁-C₄alkyl, such asethyl, isopropyl, t-butyl or preferably methyl, optionally substitutedwith one or more substituents as defined above, preferably 1-3 halo(e.g. F) or a C₁-C₄alkyloxy (e.g. methoxy) group.

In other embodiments R^(1b) is methyl, cyclopropyl, 1-phenylethyl, or a5 or 6 membered heterocyclic ring containing 1-3 nitrogen atoms and 0 or1 sulphur atoms, the cyclopropyl, phenyl or heterocyclic ring beingoptionally substituted with up to three substituents independentlyselected from:

-   -   C₁-C₄alkyl, halo, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy,        C₁-C₄alkoxycarbonyl, C₁-C₄alkylcarbonyl, amine, C₁-C₄alkylamine,        C₁-C₄-dialkylamine, C₁-C₄alkylsulfonyl, C₁-C₄alkylsulfonylamino,        aminocarbonyl, aminosulphonyl, RxOOC-C₀-C₂alkylene (where Rx is        H or C₁-C₄alkyl) or C₃-C₆cycloalkylC₀-C₂alkylene or benzyl (the        cycloalkyl, or the phenyl ring of the benzyl being optionally        substituted with 1-3 substituents selected from C₁-C₄alkyl,        halo, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy).

Examples of the 5 or 6 membered aromatic heterocyclyl for R^(1b) includepyridyl or pyrimidyl and especially pyrrolyl, pyrazolyl, imidazolyl,thiazolyl, thiadiazolyl, triazolyl or tetrazolyl, optionally substitutedwith any of which is optionally substituted with C₁-C₄alkyl (e.g. Me),halo (e.g. F), C₁-C₄haloalkyl (e.g. CF₃), C₁-C₄alkoxy (e.g. MeO),C₃-C₆cycloalkylC₀-C₁alkylene (e.g. cyclopropyl or cyclopropylmethyl,benzyl or C₀-C₂alkyleneCOOH and its C₁-C₄alkyl esters. An exemplaryspecies is 1-methyl-pyrazol-5-yl.

Typically according to this embodiment, the heterocyclic ring ispyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, or thiadiazolyl,any of which is optionally substituted with C₁-C₄alkyl, halo,C₁-C₄haloalkyl, C₁-C₄alkoxy, C₃-C₆cycloalkyl or C₃-C₆cycloalkylmethyl.

Typically according to this embodiment, the heterocyclic ring ispyrazol-1-yl, optionally substituted with C₁-C₄alkyl, halo,C₁-C₄haloalkyl or cyclopropyl.

A further typical value for R^(1b) according to this embodiment, ismethyl or cyclopropyl.

In other embodiments R^(1a) is H and R^(1b) is methyl or ethyl which issubstituted in the 1-position with a cyclic group such as phenyl, orR^(1b) is a monocyclic heterocyclyl such as pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl,tetrahydrofuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrazolyl,pyrazolyl, indolyl and the like. The phenyl or heterocyclyl isoptionally substituted, for example with 1-3 substituents independentlyselected from hydroxy, amino, C₁-C₄alkyl, halo, C₁-C₄haloalkyl,C₁-C₄alkoxy, amino, C₁-C₄alkylamine, C₁-C₄dialkylamine and the like. Anexemplary species is 1-phenylethyl.

In other embodiments R^(1a) is H and R^(1b) is C₃-C₆cycloalkyl,preferably cyclobutyl or cyclopropyl, optionally substituted as definedabove. Preferably the cycloalkyl is unsubstituted or substituted with1-3 substituents selected from halo (e.g. 1 or 2 fluoro), hydroxy, C₁-C₄alkyl (e.g. 1 or 2 methyl), C₁-C₄haloalkyl (e.g. a CF₃ group)C₁-C₄alkoxy (e.g. an MeO group), C₁-C₄alkylamine (e.g. an —NHMe group)),C₁-C₄-dialkylamine (e.g. an —N(Me)₂ group) and the like. An exemplaryspecies is cyclopropyl, or mono- or gem fluorocyclopropyl.

In some embodiments, R^(1a) is H and R^(1b) is a 6 or preferably 5membered aromatic, heterocyclic ring containing 1-3 nitrogen atoms and 0or 1 sulphur atoms, optionally substituted as defined above. Preferablythe heterocyclic ring is linked to the adjacent nitrogen of the alphaketo amide group through a carbon atom of the heterocyclic ring.Exemplary substituents include C₁-C₄ alkyl, halo, C₁-C₄ haloalkyl,C₁-C₄alkoxy, C₁-C₄ haloalkoxy, C₁-C₄alkoxycarbonyl, C₁-C₄alkylcarbonyl,amine, C₁-C₄alkylamine, C₁-C₄-dialkylamine, C₁-C₄alkylsulfonyl,C₁-C₄alkylsulfonylamino, aminocarbonyl, aminosulphonyl,RxOOC-C₀-C₂alkylene (where Rx is H or C₁-C₄alkyl) or C₃-C₆cycloalkylC₀-C₂alkylene or benzyl (the cycloalkyl or phenyl ring of thebenzyl group being optionally substituted with 1-3 substituents selectedfrom C₁-C₄ alkyl, halo, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy)

In some embodiments, R^(1a) and R^(1b) and the N atom to which they areattached form a 3-6 membered cyclic amine, such as aziridine, azetidine,pyrrolidine, and preferably morpholine, piperazine or piperidine. Thesecyclic amines may be unsubstituted or substituted as described above,preferably with 1-3 substituents selected from halo (e.g. 1 or 2fluoro), hydroxy, C₁-C₄ alkyl (e.g. 1 or 2 methyl), C₁-C₄haloalkyl (e.g.a CF₃ group) C₁-C₄alkoxy (e.g. an MeO group), C₁-C₄alkylamine (e.g. an—NHMe group), C₁-C₄-dialkylamine (e.g. an —N(Me)₂ group) and the like.

In certain embodiments R^(2a) and R^(2b) are both hydrogen. At present,however, it is preferred that at least one of R^(2a) and R^(2b) aresubstituted as defined above.

Further preferred embodiments include compounds wherein one of R^(2a)and R^(2b) is H, and the other is Cl, F, CF₃ or MeO.

In other embodiments one of R^(2a) and R^(2b) is H, and the other is F.Specially preferred according to this embodiment are compounds havingthe stereochemistry shown in the formula:

In some embodiments, R^(2a) and R^(2b) are both F. Compounds of thisaspect have the formula:

In other embodiments one of R^(2a) is and R^(2b) is H, and the other ischloro, fluoro, trifluoromethyl or methoxy.

In other embodiments R^(2a) and R^(2b) together with the carbon atom towhich they are attached form a C₃-C₆cycloalkyl;

Some embodiments have R³ as cycloalkylalkyl, optionally substituted, forexample with halo, (such as F) or alkoxy (such as MeO). Exemplaryspecies include 1-methylcyclopentylmethyl, 1-methylcyclohexylmethyl,1-methylcyclobutylmethyl, 1-methyl-3,3-difluorocyclobutylmethyl,1-methyl-4,4- difluorocyclohexylmethyl, cyclopropylmethyl, or1-methyl-3,3-difluorocyclopentylmethyl.

Preferred R³ species include t-butylmethyl or cyclobutylmethyl, or1-methylcyclobutylmethyl or 1-methylcyclopentylmethyl, any of which isoptionally substituted with one or two F or OMe. Representative speciesare 1-fluorocyclobutylmethyl and 1-fluorocyclopentylmethyl.

Other embodiments have R³ as a straight or branched chain alkyl of 5-10carbon atoms, optionally substituted with 1-4 halo, (e.g. Cl or F), or aC₁-C₄alkoxy (e.g. MeO). Exemplary species include 2,2-dimethylpropyl,3,3-dimethylpentyl, 2,2,3,3- tetramethylbutyl. Exemplary species ofhalogenated alkyl include 2,2-dichioroethyl, 3,3,3-trifluoropropyl,2,2-trifluoromethylethyl and 2,2,2-trifluoroethyl.

In some embodiments, R⁴ is morpholinyl, piperidinyl, piperazinyl,cyclopentyl, cyclohexyl or pyridinyl, any of which is optionallysubstituted with halo, hydroxy, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, amino, C₁-C₄alkylamino, di(C₁-C₄-alkyl)amino orNRkS(═O)_(m)Rq;

-   -   where Rk is H or C₁-C₄alkyl;    -   Rq is C₁-C₄alkyl, Het or Carbocyclyl, any of which is optionally        substituted with C₁-C₄alkyl, halo, C₁-C₄haloalkyl, C₁-C₄ alkoxy;        and    -   m is 0, 1 or 2.

In other embodiments R⁴ is an optionally substituted thiazolyl, such asthiazol-5-yl, optionally substituted with C₁-C₄ alkyl (e.g. Me) halo(e.g. F) or C₁-C₄alkoxy (e.g. MeO).

In other embodiments R4 is morpholi-4-yl.

In some embodiments, R⁴ is linked to the adjacent backbone amide througha ring nitrogen, thereby defining a urea function. A representativespecies is morpholin-4-yl. A further representative species has thepartial structure:

where X is C and Rt is hydroxy, fluoro, C₁-C₄alkyl, e.g. gem-methyl,C₁-C₄alkoxy (e.g. MeO) C₁-C₄haloalkyl (e.g. CF₃) or an NRk-S(═O)₂Rsfunction where Rs is C₁-C₄ alkyl, Het or Carbocyclyl, any of which isoptionally substituted with 1-3 C₁-C₄alkyl (e.g. Me), halo (e.g. F),C₁-C₄haloalkyl (e.g. CF₃), or C₁-C₄ alkoxy (e.g. MeO). Alternatively Xis N and Rt is C₁-C₄alkyl (e.g. Me) or an —NRk-S(═O)₂Rs function whereRs is C₁-C₄alkyl, Het or Carbocyclyl, any of which is optionallysubstituted with 1-3 C₁-C₄alkyl (e.g. Me), halo (e.g. F), C₁-C₄haloalkyl(e.g. CF₃), or C₁-C₄alkoxy (e.g. MeO).

In some embodiments R⁴ is piperazin-1-yl or piperidin-1-yl, either ofwhich is substituted at the 4 position or piperidin-4-yl substituted atthe 1 position; in each case the substituent is selected fromNHS(═O)₂Carbocyclyl or NHS(═O))Het, wherein the carbocyclyl or Het isoptionally substituted with halo, C₁-C₄alkyl, C₁-C₄haloalkyl orC₁-C₄alkyoxy.

In other embodiments, R⁴ is cyclohexyl or piperazin-1-yl substituted atthe 4 position with halo, amino, C₁-C₄alkylamino di-(C₁-C₄alkyl)amino orhydroxy.

In some embodiments R⁴ phenyl which is substituted with 1-3 substituentsindependently selected from halo, hydroxy, C₁-C₄alkyl, C₁-C₄haloalkyl,cyano, C₁-C₄alkylC(═O)NH— and C₁-C₄alkoxy.

Representative species include phenyl substituted with m-fluoro,p-fluoro, p-hydroxy, p-hydroxy-m-chloro, p-hydroxy-m-fluoro,p-hydroxy-m-methoxy, p-hydroxy-m-methyl, bis-p-chloro-p-hydroxy,m-cyano, p-acetamido or o-fluoro-p-hydroxy.

As defined above, R⁴ may be substituted with a group of the formulaX—R⁵, where R⁵ is H, optionally substituted C₁-C₄alkyl or an optionallysubstituted monocyclic ring which is spaced from the R⁴ ring by thedivalent X linker.

Linker X may comprise a straight chain C₁-C₄alkylene, such as ethyleneor methylene. Alternatively, the linker may comprise a divalent functionselected from CH(CH₃), C(CH₃)₂, CF₂, ethene, ethyne, C₀-C₄alkylamine,C₀-C₄alkylamide, sulphonamide, ester, ether, urea or carbamate, whichmay be bonded direct to R⁴ and/or R⁵ or may have one or more methylenegroups between the function and R⁴ and/or between the function and R⁵.The total length of the linker (including any methylene groups betweenthe function and R⁴ and/or R⁵ is 1-4 chain atoms, preferably one tothree.

Divalent functions in the X-linker containing multiple hetero atoms,such as amide, sulphonamide, ester or carbamate may be disposed ineither orientation, for example —O(C═O)NH— or —NH(═O)O— in the case of acarbamate. The expressions C₀-C₄alkylamine and C₀-C₄alkylamide in thecontext of the X-linker mean that an alkyl group (or H in the case ofC₀) branches from the nitrogen atom, for example —NH—, —N(CH₃)—,—NHC(═O)—, —N(CH₃)C(═O), —C(═O)N(CH₃)— etc.

Still further R⁴ groups include those described in WO0664206 thecontents of which are incorporated by reference. Notable R⁴ groups fromthis reference include those with the partial structures:

wherein

R^(4′) is H, halo, OC₁-C₄alkyl, C(═O)NRkRl, NRkC(═O)C₁-C₄alkyl,NRkC(═O)NRkRl or —NRkC(═O)OC₁-C₄alkyl, or NHC(═O)OMe,

Rk and Rl are independently H, C₁-C₄alkyl or C(═O)C₁-C₄alkyl or Rk, Rland an adjacent N atom to which they are both attached defines a cyclicamine selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinylor N-methylpiperazinyl.

Favoured subsets include those wherein R^(4′) is fluoro, methoxy,dimethylcarbamoyl, NHC(═O)Me, —NHC(═O)NHCH₃, NHC(═O)N(CH₃)₂, NHC(═O)OMeor a cyclic amine.

Other R⁴ embodiments within WO0664206 have the partial structures:

where Rm is —NRaSO_(m)R⁵ or —NHC(═O)NRkRl;

Rk, Rl and the N atom to which they are both attached defines a cyclicamine selected from pyrrolidinyl, piperidinyl, morpholinyl, piperazinylor N-methylpiperazinyl;

and R^(4″) is H, C₁-C₄alkyl, C₁-C₄haloalkyl, halo, cyano, hydroxyl orC₁-C₄alkoxy.

Favoured subsets include those wherein R⁵ is C₁-C₄alkyl, such as methyl,ethyl or i-propyl or t-butyl; halogenated C₁-C₄alkyl such astrifluoromethyl; C₃-C₆cycloalkyl, such as cyclopropyl or cyclohexyl; orphenyl or benzyl, any of which is optionally substituted withC₁-C₄alkyl, C₁-C₄haloalkyl, halo, cyano, C₁-C₄alkoxy.

Other R⁴ embodiments within WO0664206 have the partial structures:

where Rx is independently selected from Me, F, Cl, CF₃ and OMe, and n isindependently 0, 1 or 2.

A favoured subset has the partial structure:

Ra is H or methyl,

Rp is H, Me, F,

Rx is independently selected from Me, F, Cl, CF₃ and OMe, and n is 0, 1or 2;

especially with the partial structure:

where Rx is H, F, Me.

Still further R⁴ groups described in WO06/64206 include:

where Rx is H, F, Cl, CF₃, Me, OMe, Rz is CH, NH, NMe or O and the Satom is optionally oxidised to >S═O or preferably >S(═O)₂.

Still further R⁴ groups described in WO06/64206 include:

where Ry is H, C₁-C₄alkyl, amino, NHC₁-C₄alkyl (such as methylamino),N(C₁-C₄alkyl)₂ such as dimethylamino), NHC(═O)C₁-C₄alkyl (such asacetamido);

ring nitrogens are optionally substituted with C₁-C₄alkyl (such asmethyl, ethyl or t-butyl), or C(═O)C₁-C₄alkyl (such as acetyl); and

Rx is H, F, Cl, CF₃, Me, OMe.

Still further R⁴ groups described in WO06/64206 include:

where Rx is independently H, F, Cl CF₃ or OMe;

one or both ring nitrogens are optionally substituted with C₁-C₄alkyl(such as methyl, ethyl or t-butyl), or C(═O)C₁-C₄ alkyl (such asacetyl);

O′ is absent (i.e. 2 hydrogen atoms) or O.

Further typical R⁴ group include:

wherein Het* is a 5 or 6-membered, saturated, partially unsaturated oraromatic heterocycle containing 1-3 heteroatoms independently selectedfrom S, O and N

The compounds of formula I are characterised by various advantageouspharmaceutical properties and exhibit at least one improved property inview of the compounds of the prior art. In particular, the inhibitors ofthe present invention are superior in one or more of the followingpharmacological related properties, i.e. potency, decreasedcytotoxicity, improved pharmacokinetics, acceptable dosage and pillburden.

Without in any way wishing to be bound by theory, or the ascription oftentative binding modes for specific variables, P1, P2 and P3 as usedherein are provided for convenience only and have their conventionalmeanings and denote those portions of the inhibitor believed to fill theS1, S2 and S3 subsites respectively of the enzyme, where S1 is adjacentthe cleavage site and S3 remote from the cleavage site.

A further aspect of the invention comprises a method employing thecompounds of formula I for the prophylaxis or treatment of diseasescaused by aberrant expression or activation of cathepsin, i.e. diseasesor conditions alleviated or modified by inhibition of cathepsin S,preferably without substantial concomitant inhibition of other membersof the papain superfamily.

A further aspect of the invention provides the use of the compounds offormula I prophylaxis or treatment of diseases caused by aberrantexpression or activation of cathepsin, ie diseases or conditionsalleviated or modified by inhibition of cathepsin S, preferably withoutsubstantial concomitant inhibition of other members of the papainsuperfamily.

A further aspect of the invention provides the use of the compounds offormula I for the manufacture of a medicament for the prophylaxis ortreatment of diseases caused by aberrant expression or activation ofcathepsin S, i.e. diseases or conditions alleviated or modified byinhibition of cathepsin S, preferably without substantial concomitantinhibition of other members of the papain superfamily.

Examples of such diseases or conditions defined in the immediatelypreceding three paragraphs include those enumerated in WO 97/40066, suchas autoimmune diseases, allergies, such as asthma and hayfever, multiplesclerosis, rheumatoid arthritis and the like. A further example is thetreatment of endometriasis, and especially chronic pain, as disclosed inWO03/20287. The invention further provides the use of the compounds offormula IV in therapy and in the manufacture of a medicament for thetreatment of diseases or conditions alleviated or moderated byinhibition of cathepsin S.

In one series of embodiments, the methods are employed to treat mammals,particularly humans at risk of, or afflicted with, autoimmune disease.By autoimmunity is meant the phenomenon in which the host's immuneresponse is turned against its own constituent parts, resulting inpathology. Many human autoimmune diseases are associated with certainclass II MHC-complexes. This association occurs because the structuresrecognized by T cells, the cells that cause autoimmunity, are complexescomprised of class II MHC molecules and antigenic peptides. Autoimmunedisease can result when T cells react with the host's class II MHCmolecules when complexed with peptides derived from the host's own geneproducts. If these class II MHC/antigenic peptide complexes areinhibited from being formed, the autoimmune response is reduced orsuppressed. Any autoimmune disease in which class II MHC/antigeniccomplexes play a role may be treated according to the methods of thepresent invention.

Such autoimmune diseases include, e.g., juvenile onset diabetes (insulindependent), multiple sclerosis, pemphigus vulgaris, Graves' disease,myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritisand Hashimoto's thyroiditis.

In another series of embodiments, the methods are employed to treatmammals, particularly humans, at risk of, or afflicted with, allergicresponses. By “allergic response” is meant the phenomenon in which thehost's immune response to a particular antigen is unnecessary ordisproportionate, resulting in pathology. Allergies are well known inthe art, and the term “allergic response” is used herein in accordancewith standard usage in the medical field.

Examples of allergies include, but are not limited to, allergies topollen, “ragweed,” shellfish, domestic animals (e.g., cats and dogs),bee venom, house dust mite allergens and the like. Another particularlycontemplated allergic response is that which causes asthma. Allergicresponses may occur, in man, because T cells recognize particular classII MHC/antigenic peptide complexes. If these class II MHC/antigenicpeptide complexes are inhibited from being formed, the allergic responseis reduced or suppressed. Any allergic response in which class IIMHC/antigenic peptide complexes play a role may be treated according tothe methods of the present invention Immunosuppression by the methods ofthe present invention will typically be a prophylactic or therapeutictreatment for severe or life-threatening allergic responses, as mayarise during asthmatic attacks or anaphylactic shock.

In another series of embodiments, the methods are employed to treatmammals, particularly humans, which have undergone, or are about toundergo, an organ transplant or tissue graft. In tissue transplantation(e.g., kidney, lung, liver, heart) or skin grafting, when there is amismatch between the class II MHC genotypes (HLA types) of the donor andrecipient, there may be a severe “allogeneic” immune response againstthe donor tissues which results from the presence of non-self orallogeneic class II MHC molecules presenting antigenic peptides on thesurface of donor cells. To the extent that this response is dependentupon the formation of class II MHC/antigenic peptide complexes,inhibition of cathepsin S may suppress this response and mitigate thetissue rejection. An inhibitor of cathepsin S can be used alone or inconjunction with other therapeutic agents, e.g., as an adjunct tocyclosporin A and/or antilymphocyte gamma globulin, to achieveimmunosuppression and promote graft survival. Preferably, administrationis accomplished by systemic application to the host before and/or aftersurgery. Alternatively or in addition, perfusion of the donor organ ortissue, either prior or subsequent to transplantation or grafting, maybe effective.

The above embodiments have been illustrated with an MHC class IImechanism but the invention is not limited to this mechanism of action.Suppression of cathepsin S as a treatment of COPD or chronic pain maynot, for example, involve MHC class II at all.

A related aspect of the invention is directed to a method of treating apatient undergoing a therapy wherein the therapy causes an immuneresponse, preferably a deleterious immune response, in the patientcomprising administering to the patient a compound of Formula I or apharmaceutically acceptable salt, n-oxide or hydrate thereof. Typically,the immune response is mediated by MHC class II molecules. The compoundof this invention can be administered prior to, simultaneously, or afterthe therapy. Typically, the therapy involves treatment with a biologic,such as a protein, preferably an antibody, more preferably a monoclonalantibody. More preferrably, the biologic is Remicade®, Refacto®,ReferonA®, Factor VIII, Factor VII, Betaseron®, Epogen®, Enbrel®,Interferon beta, Botox®, Fabrazyme®, Elspar®, Cerezyme®, Myobloc®,Aldurazyrne®, Verluma®, Interferon alpha, Humira®, Aranesp®, Zevalin® orOKT3. Alternatively the treatment involves use of heparin, low molecularweight heparin, procainamide or hydralazine.

Assays for the assessment of cathepsin S inhibitors in the treatment ofchronic pain, including neuropathic or inflammatory pain are asdescribed in WO 03/20287.

Currently preferred indications treatable in accordance with the presentinvention include:

Psoriasis;

Autoimmune indications, including idiopathic thrombocytopenic purpura(ITP), rheumatoid arthritis (RA), multiple schlerosis (MS), myastheniagravis (MG), Sjögrens syndrome, Grave's disease and systemic lupuserythematosis (SLE);

Non-automimmune indications include allergic rhinitis, asthma,artherosclerosis, chronic obstructive pulmonary disease (COPD) andchronic pain.

The compounds of the invention can form salts which form an additionalaspect of the invention. Appropriate pharmaceutically acceptable saltsof the compounds of the invention include salts of organic acids,especially carboxylic acids, including but not limited to acetate,trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate,malate, pantothenate, isethionate, adipate, alginate, aspartate,benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate,glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate,palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate,tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate,organic sulphonic acids such as methanesulphonate, ethanesulphonate,2-hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesulphonate,benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate;and inorganic acids such as hydrochloride, hydrobromide, hydroiodide,sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoricand sulphonic acids.

The compounds of the invention may in some cases be isolated as thehydrate. Hydrates are typically prepared by recrystallisation from anaqueous/organic solvent mixture using organic solvents such as dioxin,tetrahydrofuran or methanol. Hydrates can also be generated in situ byadministration of the corresponding keton to a patient.

The N-oxides of compounds of the invention can be prepared by methodsknown to those of ordinary skill in the art. For example, N-oxides canbe prepared by treating an unoxidized form of the compound of theinvention with an oxidizing agent (e.g., trifluoroperacetic acid,permaleic acid, perbenzoic acid, peracetic acid,meta-chloroperoxybenzoic acid, or the like) in a suitable inert organicsolvent (e.g., a halogenated hydrocarbon such as dichloromethane) atapproximately 0° C. Alternatively, the N-oxides of the compounds of theinvention can be prepared from the N-oxide of an appropriate startingmaterial.

Compounds of the invention in unoxidized form can be prepared fromN-oxides of the corresponding compounds of the invention by treatingwith a reducing agent (e.g., sulphur, sulphur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorusbichloride, tribromide, or the like) in an suitable inert organicsolvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0to 80° C.

The present invention also includes isotope-labelled compounds offormula I or any subgroup of formula I, wherein one or more of the atomsis replaced by an isotope of that atom, i.e. an atom having the sameatomic number as, but an atomic mass different from, the one(s)typically found in nature. Examples of isotopes that may be incorporatedinto the compounds of formula I or any subgroup of formula I, includebut are not limited to isotopes of hydrogen, such as ²H and ³H (alsodenoted D for deuterium and T for tritium respectively), carbon, such as¹¹C, ¹³C and ¹⁴C, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O,¹⁷O and ¹⁸O, phosphorus, such as ³¹P and ³²P, sulphur, such as ³⁵S,fluorine, such as ¹⁸F, chlorine, such as ³⁶Cl, bromine such as ⁷⁵Br,⁷⁶Br, ⁷⁷Br and ⁸²Br, and iodine, such as ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I.

The choice of isotope included in an isotope-labelled compound willdepend on the specific application of that compound. For example, fordrug or substrate tissue distribution assays, compounds wherein aradioactive isotope such as ³H or ¹⁴C is incorporated will generally bemost useful. For radio-imaging applications, for example positronemission tomography (PET) a positron emitting isotope such as ¹¹C, ¹⁸F,¹³N or ¹⁵O will be useful. The incorporation of a heavier isotope, suchas deuterium, i.e. ²H, may provide greater metabolic stability to acompound of formula I or any subgroup of formula I, which may result in,for example, an increased in vivo half life of the compound or reduceddosage requirements.

Isotopically labelled compounds of formula I or any subgroup of formulaI can be prepared by processes analogous to those described in theSchemes and/or Examples herein below by using the appropriateisotopically labelled reagent or starting material instead of thecorresponding non-isotopically labelled reagent or starting material, orby conventional techniques known to those skilled in the art.

It should be noted that the radical positions on any molecular moietyused in the definitions may be anywhere on such moiety as long as it ischemically stable.

As used herein, the following terms have the meanings as defined below:

C_(m)-C_(n)alkyl used on its own or in composite expressions such asC_(m)-C_(n)haloalkyl, C_(m)-C_(n)alkylcarbonyl, C_(m)-C_(n)alkylamine,C_(m)-C_(n)alkylsulphonyl, C_(m)-C_(n)alkylsufonylamino etc. representsa straight or branched alkyl radical having the number of carbon atomsdesignated, e.g. C₁-C₄alkyl means an alkyl radical having from 1 to 4carbon atoms. Preferred alkyl radicals for use in the present inventionare C₁-C₄alkyl and includes methyl, ethyl, n-propyl, isopropyl, t-butyl,n-butyl and isobutyl. Methyl and t-butyl are typically preferred.C₁-C₆alkyl has a corresponding meaning, including also all straight andbranched chain isomers of pentyl and hexyl. Other recitals ofC_(m)-C_(n)alkyl, such as C₅-C₁₀ alkyl have the corresponding meaning.

The term Me means methyl, MeO means methoxy, Et means ethyl and Ac meansacetyl.

C₀-C₂alkylene used in composite expressions such asC₃-C₆cycloalkylC₀-C₂alkylene refers to a divalent radical derived from amethyl or ethyl group, or in the case of C₀ the term C₀-C₂alkylene meansa bond.

C₁-C₄haloalkyl refers to C₁-C₄ alkyl, wherein at least one C atom issubstituted with a halogen, preferably chloro or fluoro. Trifluoromethylis typically preferred.

C₁-C₄alkoxy represents a radical C₁-C₄alkyl-O wherein C₁-C₄alkyl is asdefined above, and includes methoxy, ethoxy, n-propoxy, isopropoxy,t-butoxy, n-butoxy and isobutoxy. Methoxy and isopropoxy are typicallypreferred. C₁-C₆alkoxy has a corresponding meaning, expanded to includeall straight and branched chain isomers of pentoxy and hexoxy. Otherrecitals of C_(m)-C_(n)alkoxy, such as C₅-C₁₀alkoxy have thecorresponding meaning.

C₁-C₄haloalkoxy as used herein is meant to include C₁-C₄alkoxy whereinat least one C-atom is substituted with one or more halogen atom(s),typically chloro or fluoro. In many cases trifluoromethyl is preferred.

C₁-C₄alkoxycarbonyl means a radical C₁-C₄alkyl-O—C(═O).

The term “oxo” represents ═O, i.e. a carbonyl group is formed whenattached to a carbon atom.

Carbocyclyl includes cyclopentyl, cyclohexyl and especially cyclopropyland cyclobutyl. Carbocyclyl further includes cyclopentenyl andcyclohexenyl, in each case with a single double bond. A frequentlypreferred value for Carbocyclyl is phenyl.

Cyclic amine includes aziridine, azetidine, pyrrolidine, piperidine,piperazine and morpholinyl.

Het is a stable, monocyclic or bicyclic, saturated, partially saturatedor aromatic ring system, containing 1-4 hetero atoms independentlyselected from O, S and N, and each ring having 5 or 6 ring atoms;Exemplary aromatic Het include furan, thiophene, pyrrole, imidazole,pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole,thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine,quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazoleand the like. Exemplary unsaturated Het include tetrahydrofuran, pyran,dihydropyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine,morpholine, tetrahydrothiopyran, tetrahydrothiophene, 2-H-pyrrole,pyrroline, pyrazoline, imidazoline, thiazolidine, isoxazolidine and thelike.

The compounds of the invention include a number of handles such as OH,NH or COOH groups to which conventional prodrug moieties can be applied.Prodrugs are typically hydrolysed in vivo to release the parent compoundin the plasma, liver or intestinal wall. Favoured prodrugs are esters ofhydroxyl groups such as a phenolic hydroxyl group at R⁴, or aminefunctions such as a sulphonamide amine function. Preferredpharmaceutically acceptable esters include those derived from C₁-C₆carboxylic acids such as acetyl or pivaloyl or optionally substitutedbenzoic acid esters, preferably unsubstituted or substituted withsubstituents broadly as described for R^(1a), typically 1-3 halo (e.g.F), C₁-C₄alkyl (e.g. Me), C₁-C₄haloalkyl (e.g. CF₃) or C₁-C₄alkyloxy(e.g. MeO) groups. Favoured sulphonamide prodrugs include aminoacylsderived from C₁-C₆ carboxylic acids such as acetyl or pivaloyl oroptionally substituted benzoic acid esters, preferably unsubstituted orsubstituted with substituents broadly as described for variable R^(1a),typically 1-3 halo (e.g. F), C₁-C₄alkyl (e.g. Me), C₁-C₄haloalkyl (e.g.CF₃) or C₁-C₄alkyloxy (e.g. MeO) groups.

Unless otherwise mentioned or indicated, the chemical designation of acompound encompasses the mixture of all possible stereochemicallyisomeric forms, which said compound may possess. Said mixture maycontain all diastereomers and/or enantiomers of the basic molecularstructure of said compound. All stereochemically isomeric forms of thecompounds of the present invention both in pure form or mixed with eachother are intended to be embraced within the scope of the presentinvention.

Pure stereoisomeric forms of the compounds and intermediates asmentioned herein are defined as isomers substantially free of otherenantiomeric or diastereomeric forms of the same basic molecularstructure of said compounds or intermediates. In particular, the term“stereoisomerically pure” concerns compounds or intermediates having astereoisomeric excess of at least 80% (i e minimum 90% of one isomer andmaximum 10% of the other possible isomers) up to a stereoisomeric excessof 100% (i.e. 100% of one isomer and none of the other), more inparticular, compounds or intermediates having a stereoisomeric excess of90% up to 100%, even more in particular having a stereoisomeric excessof 94% up to 100% and most in particular having a stereoisomeric excessof 97% up to 100%. The terms “enantiomerically pure” and“diastereomerically pure” should be understood in a similar way, butthen having regard to the enantiomeric excess, and the diastereomericexcess, respectively, of the mixture in question.

Compounds of the invention can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomer. While resolution of enantiomers can be carried outusing covalent diasteromeric derivatives of compounds of Formula I,dissociable complexes are preferred (e.g., crystalline;diastereoisomeric salts). Diastereomers have distinct physicalproperties (e.g., melting points, boiling points, solubilities,reactivity, etc.) and can be readily separated by taking advantage ofthese dissimilarities. The diastereomers can be separated bychromatography, for example HPLC or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

While it is possible for the active agent to be administered alone, itis preferable to present it as part of a pharmaceutical formulation.Such a formulation will comprise the above defined active agent togetherwith one or more acceptable carriers/excipients and optionally othertherapeutic ingredients. The carrier(s) must be acceptable in the senseof being compatible with the other ingredients of the formulation andnot deleterious to the recipient.

The formulations include those suitable for rectal, nasal, topical(including buccal and sublingual), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous and intradermal)administration, but preferably the formulation is an orally administeredformulation. The formulations may conveniently be presented in unitdosage form, e.g. tablets and sustained release capsules, and may beprepared by any methods well known in the art of pharmacy. Such methodsinclude the step of bringing into association the above defined activeagent with the carrier. In general, the formulations are prepared byuniformly and intimately bringing into association the active agent withliquid carriers or finely divided solid carriers or both, and then ifnecessary shaping the product. The invention extends to methods forpreparing a pharmaceutical composition comprising bringing a compound ofFormula I or its pharmaceutically acceptable salt in conjunction orassociation with a pharmaceutically acceptable carrier or vehicle. Ifthe manufacture of pharmaceutical formulations involves intimate mixingof pharmaceutical excipients and the active ingredient in salt form,then it is often preferred to use excipients which are non-basic innature, i.e. either acidic or neutral.

Formulations for oral administration in the present invention may bepresented as discrete units such as capsules, cachets or tablets eachcontaining a predetermined amount of the active agent; as a powder orgranules; as a solution or a suspension of the active agent in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water in oil liquid emulsion and as a bolus etc.

With regard to compositions for oral administration (e.g. tablets andcapsules), the term suitable carrier includes vehicles such as commonexcipients e.g. binding agents, for example syrup, acacia, gelatin,sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose,ethylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers,for example corn starch, gelatin, lactose, sucrose, microcrystallinecellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride andalginic acid; and lubricants such as magnesium stearate, sodium stearateand other metallic stearates, glycerol stearate stearic acid, siliconefluid, talc waxes, oils and colloidal silica. Flavouring agents such aspeppermint, oil of wintergreen, cherry flavouring or the like can alsobe used. It may be desirable to add a colouring agent to make the dosageform readily identifiable. Tablets may also be coated by methods wellknown in the art.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active agent in a free flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, preservative, surface-active or dispersingagent. Moulded tablets may be made by moulding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.The tablets may be optionally be coated or scored and may be formulatedso as to provide slow or controlled release of the active agent.

Other formulations suitable for oral administration include lozengescomprising the active agent in a flavoured base, usually sucrose andacacia or tragacanth; pastilles comprising the active agent in an inertbase such as gelatin and glycerin, or sucrose and acacia; andmouthwashes comprising the active agent in a suitable liquid carrier.

As with all pharmaceuticals, the appropriate dosage for the compounds orformulations of the invention will depend upon the indication, theseverity of the disease, the size and metabolic vigour and the patient,the mode of administration and is readily determined by conventionalanimal trials. Dosages providing intracellular (for inhibition ofphysiological proteases of the papain superfamily) concentrations of theorder 0.01-100 μM, more preferably 0.01-10 μM, such as 0.1-5 μM aretypically desirable and achievable.

Compounds of the invention are prepared by a variety of solution andsolid phase chemistries.

A typical first step is the preparation of a P1 building block of theformula II

where R^(2a) and R^(2b) are as defined above, PG is a conventional Nprotecting group such as Boc, CBz or Fmoc and PG* is H or a conventionalcarboxy protecting group, such as a C₁-C₄alkyl or benzyl ester. Thesebuilding blocks are novel and constitute a further aspect of theinvention.

Building blocks of formula II are typically prepared as described inscheme 1 below.

A suitable starting material is an N-protected cyclobutyl amino acid, ofwhich several are available commercially or can be prepared as shown inthe following Examples or as described by Allan et al. in J. Med. Chem.,1990 33(10) 2905-2915.

The carboxylic acid (1a) is transformed via a Weinreb synthesis to aN,O-dimethylhydroxamic acid (1b) which provides the correspondingaldehyde (1c). The aldehyde may also be accessed by reduction of thecarboxylic function of a cyclobutyl amino acid and oxidation under DessMartin conditions. The aldehyde (1c) can be subsequently reacted withthe appropriate isocyanide in a Passerini reaction to afford therequired α-hydroxy R^(1a)R^(1b) amide where R^(1a) is H (1d). However,in the case where the appropriate isocyanide is not readily available,t-butylisocyanide can alternatively be used, thus affording the t-butylamide. Subsequent hydrolysis of the amide, then provides the requireda-hydroxycarboxylic acid P1 building block (1e). Generally the stronglyacidic conditions required to hydrolyse the amide also lead to loss ofthe NBoc protection, if used. Hence, the amine can be used directly tocouple to a P2 building block or else if it needs to be stored, theamine can be reprotected.

The P1 building block thus afforded is then extended at the C and Ntermini as shown in scheme 2 below.

Typically the C terminus is extended first by reaction of the buildingblock of formula II with the R^(1a*) R^(1b*) amine, where R^(1a*) andR^(1b*) are R^(1a) and R^(1b) respectively or synthons therefor(selected in view of the sensitivity of the R^(1b) function for the P3elongation conditions outlined below). The reaction proceeds withconventional peptide chemistries as discussed below. The thus preparedP1-prime side unit is thereafter deprotected at the N terminus andelongated with the P2 and subsequently P3 building blocks usingconventional peptide chemistries. For example a P2 residue can beintroduced via BocP2-OH using standard coupling conditions such as HATU,DIPEA in DMF. The terminal Boc protection is again removed with acetylchloride in methanol and the P3 residue introduced via P3-OH usingstandard coupling conditions such as HATU, DIPEA in DMF.

An extensive range of appropriately protected L-amino acids suitable forP2 building blocks or carbocyclic or heterocyclic carboxylic acidssuitable for P3 building blocks are commercially available or accessedby simple chemistries or as shown in WO06/064286. The P3 and P2 buildingblocks may alternatively be coupled first and then reacted with theP1-prime side unit.

The final steps will generally comprise conversion of theR^(4*)/R^(1a*)/R^(1b*) synthons (if present) to their final form andfinally oxidation of the alpha hydroxy amide function using Dess Martinconditions to provide the desired alpha keto amide compound of formulaI.

Elongation is typically carried out in the presence of a suitablecoupling agent e.g., benzotriazole-1-yloxytrispyrrolidinophosphoniumhexafluorophosphate (PyBOP),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate(HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uroniumhexafluorophosphate (HATU),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), or1,3-dicyclohexyl carbodiimide (DCC), optionally in the presence of1-hydroxybenzotriazole (HOBT), and a base such asN,N-diisopropylethylamine, triethylamine, N-methylmorpholine, and thelike. The reaction is typically carried out at 20 to 30° C., preferablyat about 25° C., and requires 2 to 24 h to complete. Suitable reactionsolvents are inert organic solvents such as halogenated organic solvents(e.g., methylene chloride, chloroform, and the like), acetonitrile,N,N-dimethylformamide, ethereal solvents such as tetrahydrofuran,dioxane, and the like.

Alternatively, the above elongation coupling step can be carried out byfirst converting the P3/P2 building block into an active acid derivativesuch as succinimide ester and then reacting it with the P1 amine. Thereaction typically requires 2 to 3 h to complete. The conditionsutilized in this reaction depend on the nature of the active acidderivative. For example, if it is an acid chloride derivative, thereaction is carried out in the presence of a suitable base (e.g.triethylamine, diisopropylethylamine, pyridine, and the like). Suitablereaction solvents are polar organic solvents such as acetonitrile,N,N-dimethylformamide, dichloromethane, or any suitable mixturesthereof.

The term “N-protecting group” or “N-protected” as used herein refers tothose groups intended to protect the N-terminus of an amino acid orpeptide or to protect an amino group against undesirable reactionsduring synthetic procedures. Commonly used N-protecting groups aredisclosed in Greene, “Protective Groups in Organic Synthesis” (JohnWiley & Sons, New York, 1981), which is hereby incorporated byreference. N-protecting groups include acyl groups such as formyl,acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl,2-bromoacetyl, trifluoracetyl, trichloroacetyl, phthalyl,o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl,4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such asbenzenesulfonyl, p-toluenesulfonyl, and the like, carbamate forminggroups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and thelike; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl andthe like; and silyl groups such as trimethylsilyl and the like. FavouredN-protecting groups include formyl, acetyl, benzoyl, pivaloyl,t-butylacetyl, phenylsulfonyl, benzyl (bz), t-butoxycarbonyl (BOC) andbenzyloxycarbonyl (Cbz).

Hydroxy and/or carboxy protecting groups are also extensively reviewedin Greene ibid and include ethers such as methyl, substituted methylethers such as methoxymethyl, methylthiomethyl, benzyloxymethyl,t-butoxymethyl, 2-methoxyethoxymethyl and the like, silyl ethers such astrimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS) tribenzylsilyl,triphenylsilyl, t-butyldiphenylsilyl triisopropyl silyl and the like,substituted ethyl ethers such as 1-ethoxymethyl,1-methyl-1-methoxyethyl, t-butyl, allyl, benzyl, p-methoxybenzyl,dipehenylmethyl, triphenylmethyl and the like, aralkyl groups such astrityl, and pixyl (9-hydroxy-9-phenylxanthene derivatives, especiallythe chloride). Ester hydroxy protecting groups include esters such asformate, benzylformate, chloroacetate, methoxyacetate, phenoxyacetate,pivaloate, adamantoate, mesitoate, benzoate and the like. Carbonatehydroxy protecting groups include methyl vinyl, allyl, cinnamyl, benzyland the like.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Various embodiments of the invention will now be described by way ofillustration only with reference to the following Examples.

In the examples below, the following systems are typically employed:Nuclear Magnetic Resonance (NMR) spectra were recorded on a VarianGemini 7 Tesla 300 MHz instrument, or a Bruker Avance 400 MHz instrumentin the solvent indicated. Chemical shifts are given in ppm down- andupfield from tetramethylsilane (TMS). Resonance multiplicities aredenoted s, d, t, m, br and app for singlet, doublet, triplet, multiplet,broad and apparent, respectively. The Mass Spectrometry (MS) spectrawere recorded on a Finnigan SSQ7000 TSP or a Finnigan SSQ710 DI/EIinstrument. LC-MS was obtained with a Waters 2790 LC-system equippedwith a Waters Xterra™ MS C₈ 2.5 μm 2.1×30 mm column, a Waters 996Photodiode Array Detector and a Micromass ZMD. High pressure liquidchromatography (HPLC) assays were performed using a Hewlett Packard 1100Series HPLC system equipped with a Zorbax column SB-C₈ 4.6 mm×15 cm.Column chromatography was performed using silica gel 60 (230-400 meshASTM, Merck) and thin layer chromatography (TLC) was performed on TLCprecoated plates, silica gel 60 F₂₅₄ (Merck).

Preparation of Building Block 1(BB1), a P1 Building Block

Step a) [1-(Methoxy-methyl-carbamoyl)-cyclobutyl]-carbamic Acidtert-butyl Ester (BB1-a)

To a solution of 1-tert-butoxycarbonylamino-cyclobutanecarboxylic acid(3 g, 13.94 mmol) in dry DMF (50 mL) was addedN,O-dimethylhydroxylaminexHCl (1.36 g, 13.94 mmol) and DIEA (9.21 mL,55.75 mmol). The reaction flask was cooled to 0° C. and after 10 minutesHATU (5.30 g, 13.94 mmol) was added to the solution (which turned yellowon addition). After 2 hrs the DMF was removed by rotary evaporation atreduced pressure. The residue was dissolved in 100 mL EtOAc and washedtwice with 10% citric acid (aq) and saturated NaHCO₃(aq) solution. Theorganic phase was dried with Na₂SO₄, filtered and evaporated on silica.The product was purified by flash chromatography (heptane: ethyl acetate(1:1) to give the product as a colourless oil that slowly crystallizes(3.13 g) in 87% yield.

Step b) (1-Formyl-cyclobutyl)-carbamic Acid tert-butyl Ester (BB1-b)

LiAlH₄ (202 mg, 5.33 mmol) was added to a solution of the Weinreb amideBB1-a (1.10 g, 4.27 mmol) dissolved in dry diethyl ether (35 mL) at 0°C. The solution was stirred at 15 minutes before the reaction wasquenched with slow addition of potassium hydrogen tartaric acid (sat,aq) and stirred for 10 minutes. The solution was poured into aseparatory funnel and the water phase was extracted with ethyl acetatetwice. The combined organic phases were washed with 0.5 M HCl (3 times),NaHCO₃(aq) (2 times) and brine (1 time). The organic phase was driedwith Na₂SO₄, filtered and evaporated on silica. The product was purifiedby flash chromatography (heptane: ethyl acetate (4:1→3:1) to give theproduct as white crystals (0.647 g) in 76% yield.

Step c) [1-(tert-Butylcarbamoyl-hydroxy-methyl)-cyclobutyl]-carbamicAcid tert-butyl Ester (BB1-c)

BB1-b, (1.75 g, 8.78 mmol) was dissolved in CH₂Cl₂ (18 mL) and cooled inan ice bath, under inert gas. Pyridine (2.85 mL) was added, followed byt-butyl isocyanide (1.50 mL, 13.3 mmol). Trifluoroacetic acid (1.35 mL,17.5 mmol) was then added dropwise over 30 min The yellow solution wasstirred at RT overnight. The mixture was concentrated, diluted withEtOAc (100 mL) and washed successively with 1N HCl (50 mL), saturatedNaHCO₃ (50 mL) and saturated NaCl (2×50 mL). Drying (Na₂SO₄) andconcentration under vacuum. The afforded crude product was treated withTHF (2.5 mL) and 1M LiOH in 3/1 MeOH-water (2.5 mL) at RT. TLC (3/1petroleum ether—EtOAc). After 45 min reaction time, 1N HCl (2.5 mL),water (10 mL) and EtOAc (20 mL) were added, and the layers wereseparated. The organic phase was washed with saturated NaHCO₃ (20 mL)and then saturated NaCl (2×20 mL), dried (Na₂SO₄) and concentrated.Flash chromatography (75 g silica, 5/1 to 1/1 petroleum ether:EtOAc)gave a white solid (2.36 g, 89%).

Step d (1-tert-Butoxycarbonylamino-cyclobutyl)-hydroxy-acetic Acid (BB1)

BB1-c (1.30 g, 4.33 mmol) was refluxed with 6N HCl (40 mL) until amidehydrolysis was complete as monitored by LCMS. The mixture wasevaporated, co-evaporating several times with water. 1M NaOH (15 mL) wasadded to the residue and the basic solution was stirred under vacuum for15 min. Boc₂O (1.92 g, 8.80 mmol) in dioxane (10 mL) was added, keepingpH at 10-11, and the mixture was stirred at RT overnight. The mixturewas diluted with water (50 mL), acidified with 1N HCl to pH 3, in an icebath, and then extracted with EtOAc (2×50 mL, then 30 mL). The organicphase was washed with saturated NaCl (50 mL), dried (Na₂SO₄) andevaporated to give crude P1 building block BB1 (0.649 g). ^(1H)NMR (400MHz, d₆-DMSO) δ 6.88 (br s, 1H), 4.15 (s, 1H), 2.40 (br m, 2H), 1.98 (brm, 2H), 1.80 (br m, 2H), 1.35 (s, 9H); ms ES⁺ m/z 146 (100%), 190 (50%).

Preparation of Building Block 2, an Alternative P1 Building Block (BB2)

Step a) ((1-Bromo-3-chloropropan-2-yloxy)methyl)benzene (BB2-a)

To a stirred mixture of benzyl bromide (185 g, 1.08 mol) and (1.5 g) ofmercury chloride was added epichlorohydrin (100 g, 1.08 mol). Thereaction mixture was heated for 12 hr at 100° C. TLC analysis confirmedformation of product. The product was separated from the dark brownreaction mixture by column chromatography using petroleum ether aseluent. TLC system; Petroleum ether: ethyl acetate (9:1), R_(F)=0.7.Yield; 148 g, 51%.

Step b) 3-Benzyloxy-cyclobutane-1,1-dicarboxylic Acid Diethyl Ester(BB2-b)

To a stirred suspension of sodium hydride (22.5 g, 0.562 mol) in 800 mLof dry dioxane, was added diethyl malonate (90 g 0.562 mol) drop-wiseover 20 min After this addition was complete, BB2-a (148 g, 0.56 mol)was added drop-wise over 20 min. The mixture was then heated at refluxfor 24 hr. After cooling to room temperature, sodium hydride (22.5 g,0.562 mol) in a little dioxane (˜20 mL) was added to the mixture andheating at reflux was continued for an additional 48 hr. The solvent waspartially removed under reduced pressure and the mixture was treatedwith 800 mL of water. This mixture was then extracted with ethyl acetate(500 mL×3), extracts were dried (Na₂SO₄) and concentrated in vacuo andthe residue was purified by column chromatography using petroleum ether:ethyl acetate (10%) which gave the title compound. TLC system; petroleumether: ethyl acetate (9:1), R_(F)=0.3. Yield: 100 g, 58%

Step c) Diethyl 3-hydroxycyclobutane-1,1-dicarboxylate (BB2-c)

To a solution of compound BB2-b (40 g) in EtOH (500 mL) was added 10%palladium on charcoal (4 g) and the mixture was hydrogenated for 3.5hours at 50 psi at room temperature. The catalyst was removed byfiltration, washed with ethyl acetate, EtOH and the solvent was thenremoved under reduced pressure. The residue was purified by silica gelchromatography with hexane/ ethyl acetate as eluent to provide the titlecompound. TLC system; Petroleum ether: ethyl acetate (9:1), R_(F)=0.3.Yield: 18 g, 64%.

Step d) Diethyl 3-oxocyclobutane-1,1-dicarboxylate (BB2-d)

To a solution of compound BB2-c (18 g, 0.0833 mol) in DCM (200 mL) wasadded PCC (37 g, 0.176 mol) and the mixture was stirred for four hoursat room temperature. The solution was filtered through a silica gelcolumn and the residue was washed with DCM/MeOH 98/2 and then filteredthrough a similar column. The combined fractions were evaporated underreduced pressure to provide the desired compound, (11 g, 62%).

Step e) Diethyl 3,3-difluorocyclobutane-1,1-dicarboxylate (BB2-e)

To a cooled solution of compound BB2-d (11 g, 0.0513 mol) in dry DCM(150 mL) was added drop-wise a solution of DAST (18.72 g, 0.116 mol) andthe mixture was stirred at room temperature overnight. The mixture wasadded to ice water and was extracted three times with DCM. The solutionwas dried with sodium sulphate and evaporated under reduced pressure.The residue was purified by silica gel chromatography employinghexane/ethyl acetate as eluent to provide the title compound (7.7 g,64%).

Step f) 1-(Ethoxycarbonyl)-3,3-difluorocyclobutanecarboxylic Acid(BB2-f)

Compound BB2-e (7.7 g, 0.0325 mol) was dissolved in ice cooled 0.5 Methanolic potassium hydroxide solution (30 mL) and water (6 mL). Themixture was stirred at room temperature overnight. Water was added andmost of the ethanol was removed under reduced pressure. The mixture wasacidified with 2M HCl and extracted three times with ethyl acetate. Theorganic phase was dried with sodium sulphate and evaporated underreduced pressure to give the desired compound (5.8 g, 86%).

Step g) Ethyl1-(tert-butoxycarbonylamino)-3,3-difluorocyclobutanecarboxylate (BB2-g)

To a solution of compound BB2-f (5.8 g, 0.0273 mol) in dry dioxane (100mL) was added tert-butanol (24.4 mL), DPPA (7.87 g, 0.027 mol) and TEA(2.87 g, 0.0284 mol) and the mixture was refluxed for five hours. Ethylacetate (about 200 mL) was added and the organic phase was washed twicewith 5% citric acid and saturated sodium hydrogen carbonate. Thesolution was dried and evaporated under reduced pressure. The desiredproduct was isolated by silica gel chromatography with hexane/ethylacetate, (4 g, 51.4%).

Step h) tert-Butyl 3,3-difluoro-1-(hydroxymethyl)cyclobutylcarbamate(BB2-h)

To a ice cooled solution of compound BB2-g (4 g, 0.0143 mol) in dry THF(100 mL) was slowly added a solution of 2M lithium borohydride (30 mL)and the mixture was allowed to warm up to room temperature. The mixturewas stirred for three hours at room temperature. Ice water and 5% citricacid were added and the mixture was extracted three times with DCM. Theorganic phase was dried (Na₂SO₄), filtered and evaporated under reducedpressure which gave the title compound, (3.1 g, 91%).

Step i) tert-Butyl 3,3-difluoro-1-formylcyclobutylcarbamate (BB2-i)

To a solution of compound BB2-h (3.1 g, 0.0130 mol) in dry DCM (100 mL)was added Dess Martin Period inane (19.9 g, 0.0470 mol) and the mixturewas stirred for three hours at room temperature. Ethyl acetate (200 mL)was added and the organic phase was washed twice with 10% sodiumthiosulphate solution, twice with 0.5 M NaOH and with brine. The organicphase was dried and evaporated under reduced pressure. The residue waspurified by silica gel chromatography with hexane/ethyl acetate aseluent which gave the title compound, (2.7 g, 87%).

Step j) tert-Butyl1-(2-(tert-butylamino)-1-hydroxy-2-oxoethyl)-3,3-difluorocyclobutylcarbamate(BB2-j)

To a ice cooled solution of compound BB2-i (1.5 g, 0.0064 mol) in dryDCM (100 mL) was added tert-butylisocyanate (0.81 g, 0.009 mol) andpyridine (2.04 g, 0.027 mol). Trifluoroacetic acid (1.58 g, 0.015 mol)was added over a ten minutes period. The mixture was stirred for fivehours at room temperature. Ethyl acetate was added and the organic phasewas washed twice with 5% citric acid and brine. The organic phase wasevaporated and dissolved in dioxane (50 mL). 1M LiOH solution (100 mL)was added and the mixture was stirred overnight at room temperature. 5%Citric acid was added and the mixture was extracted three times withethyl acetate. The organic phase was washed with brine, dried (Na₂SO₄),filtered and evaporated under reduced pressure. The product was purifiedby silica gel chromatography with hexane/ethyl acetate as eluent, (1.0g, 46%).

Step k)2-(1-(tert-Butoxycarbonylamino)-3,3-difluorocyclobutyl)-2-hydroxyaceticAcid (BB2)

Compound BB2-j (1 g) was dissolved in 6N HCl (40 mL), and heated toreflux for 24 h after which TLC showed that the reaction had reachedcompletion. The reaction mixture was concentrated in vacuo and residuewas dissolved in THF; H₂O (7; 3, 50 mL), and TEA (1.8 mL, 0.012 mol) andBoc anhydride (2.6 g, 0.012 mol) were both added. The mixture wasstirred at RT for 8 h when TLC confirmed the reaction had reachedcompletion. The reaction mixture was concentrated in vacuo and theresidue was purified by column chromatography using 5% methanol inchloroform which gave the title compound, (0.6 g, 72%). ^(1H)NMR (400MHz, d₆-DMSO) δ 7.30 (br s, 1H), 4.11 (s, 1H), 2.90 (br m, 2H), 2.61 (brm, 2H), 1.35 (s, 9H); ms ES⁺ m/z 281 (100%).

Preparation of Building Block 3—An Alternative P1 Building Block (BB3)

Step a) ((1-Bromo-3-chloropropan-2-yloxy)methyl)benzene (BB3-a)

A mixture of benzyl bromide (46.0 g, 0.269 mol) and epichlorohydrin(24.9 g, 0.269 mol) and mercury chloride (0.04 g, 0.085 mmol) was heatedfor 12 h at 150° C. The crude product was purified by columnchromatography (silica gel 60-120 mesh, eluent 1% EtOAc in pet ether)which afforded the title compound as a viscous liquid (50 g, yield 70%).

Step b) Diethyl 3-(benzyloxy)cyclobutane-1,1-dicarboxylate (BB3-b)

In a three-neck flask equipped with stirrer, additional funnel andreflux condenser was place NaH (4.6 g, 0.192 mol) in dry dioxane (150mL). To this stirred reaction mixture, diethyl malonate (30.75 g, 0.192mol) was added drop-wise over 30 min. After the addition was complete,compound BB3-a (50 g, 0.19 mol) was added drop-wise over a period of 30min. The reaction mixture was refluxed for 24 h. After cooling to roomtemperature, NaH (4.6 g, 0.192 mol) and dry dioxane (40 mL) was added tothe reaction mixture and further heated to reflux for another 48 h. Thesolvent was partially removed under reduced pressure and the mixture wastreated with water (150 mL). The product was extracted with diethylether (3×100 mL), the organic layer was washed with brine and dried overanhydrous Na₂SO₄. Solvent was concentrated in vacuum and the crudeproduct was purified by column chromatography (silica gel 60-120 mesh,eluent 2% EtOAc in pet ether) which afforded the title compound as aviscous liquid (33 g, yield 57%). TLC system: 15% EtOAc in pet ether,R_(f)=0.5.

Step c) Diethyl 3-hydroxycyclobutane-1,1-dicarboxylate (BB3-c)

To a solution of compound BB3-b (33 g, 0.108 mol) in EtOH (300 mL) wasadded 10% palladium on charcoal (10 g) and the mixture was hydrogenatedfor 48 h with 50 psi pressure at room temperature. The catalyst wasremoved by filtration through a Celite bed and washed thoroughly withEtOAc. The solvent was removed under reduced pressure. The product waspurified by silica gel chromatography (silica gel 60-120 mesh, eluent20% EtOAc in pet ether) which afforded product 3 as a viscous liquid (12g, yield 51%). TLC system: 30% EtOAc in pet ether, R_(f)=0.3.

Step d) Diethyl 3-fluorocyclobutane-1,1-dicarboxylate (BB3-d)

Compound BB3-c (0.8 g, 0.0037 mol) was dissolved in dry DCM (16 mL) andcooled to 0° C. DAST (1.8 g, 0.011 mol) was added drop-wise to the coldsolution. The reaction mixture was warmed to room temperature stirredfor 12 h. The reaction mixture was quenched with cold saturated NaHCO₃solution. The crude product was extracted with DCM (100 mL). The organiclayer was washed with 10% NaHCO₃ solution, water followed by brine anddried over anhydrous Na₂SO₄. Solvent was concentrated in vacuum and thecrude product was purified by column chromatography (silica gel 60-120mesh, eluent 1-2% EtOAc in pet ether) which afforded the title compoundas a pale yellow liquid (460 mg, yield 57%). TLC system: 10% EtOAc inpet ether, R_(f)=0.4.

Step e) 1-(Ethoxycarbonyl)-3-fluorocyclobutanecarboxylic Acid (BB3-e)

Compound BB3-d (0.46 g, 0.0021 mol) was dissolved in ice cooled 0.5Mpotassium hydroxide solution in EtOH (4.2 mL) and water (1.4 mL). Themixture was stirred at room temperature overnight. Water was added andmost of the ethanol was removed under reduced pressure. The mixture wasacidified with 2N HCl and extracted with EtOAc (3×50 mL). The organicphase was dried over anhydrous Na₂SO₄. Solvent was concentrated invacuum to afford the crude title compound (0.35 g, crude) which was usedas such for the next step. TLC system: 50% EtOAc in pet ether,R_(f)=0.3.

Step f) Ethyl1-(tert-butoxycarbonylamino)-3-fluorocyclobutanecarboxylate (BB3-f)

To a solution of compound BB3-e (0.35 g, 0.0018 mol) in dry dioxane (6mL) was added tert-butanol (1.8 mL), diphenyl phosphoryl azide (0.56 g,0.002 mol) and triethylamine (0.2 g, 0.002 mol) and the mixture wasrefluxed for 5 h. After completion of the reaction, EtOAc (60 mL) wasadded to the reaction mixture and the organic layer was washed with 5%citric acid (2×20mL) followed by saturated NaHCO₃ (50 mL). The organicsolvent was evaporated under reduced pressure. To the residue EtOAc (100mL) was added and the organic layer was washed with brine and dried overanhydrous Na₂SO₄. Solvent was concentrated in vacuum and the crudeproduct was purified by column chromatography (silica gel 60-120 mesh,eluent 5-10% EtOAc in pet ether) which afforded the title compound aswhite crystals (0.27 g, yield 56%). TLC system: 20% EtOAc in pet ether,R_(f)=0.4.

Step g) tert-Butyl 3-fluoro-1-(hydroxymethyl)cyclobutylcarbamate (BB3-g)

To a ice cooled solution of compound BB3-f (0.27 g, 0.001 mol) in dryTHF (10 mL) was slowly added a solution of 2M lithium borohydride (2 mL,0.004 mol) and the mixture was allowed to warm up to room temperature.The mixture was stirred for 3 h at room temperature. The reactionmixture was quenched with ice water (2 mL) and 5% citric acid (5 mL) andthe crude product was extracted with DCM (2×50mL). The organic layer waswashed with brine and dried over anhydrous Na₂SO₄. Solvent wasconcentrated in vacuum and the crude product was purified by columnchromatography (silica gel 60-120 mesh, eluent 15-18% EtOAc in petether) which afforded the title compound as white solid (90 mg, yield39%). TLC system: 50% EtOAc in pet ether, R_(f)=0.5.

Step h) tert-Butyl 3-fluoro-1-formylcyclobutylcarbamate (BB3-h)

To a degassed solution of compound BB3-g (90 mg, 0.0004 mol) in dry DCM(4.5 mL) was added Dess Martin Periodinane (0.21 g, 0.0005 mol) and themixture was stirred for 3 h at room temperature. EtOAc (30 mL) was addedand the organic layer was washed with 10% sodium thiosulphate solution(2×10mL), 0.5 M NaOH (20 mL) and with brine. The organic layer was driedover anhydrous Na₂SO₄. Solvent was concentrated in vacuum and the crudeproduct was purified by column chromatography (silica gel 60-120 mesh,eluent 10-15% EtOAc in pet ether) which afforded the title compound as awhite crystalline solid (75 mg, yield 87%).TLC system: 20% EtOAc in petether, R_(f)=0.4.

Step i) tert-Butyl1-(2-(tert-butylamino)-1-hydroxy-2-oxoethyl)-3-fluorocyclobutylcarbamate(BB3-i)

To an ice cooled solution of compound BB3-h (1.3 g, 0.0059 mol) in dryDCM (25 mL) was added tert-butyl isocyanide (0.75 g, 0.0089 mol) and drypyridine (2.6 mL). Trifluoroacetic acid (0.9 mL, 0.0118 mol) was addedover a period of ten minutes maintaining the temperature at 0° C. Thereaction mixture was slowly warmed to room temperature and stirred for16 h.

EtOAc (50 mL) was added and the organic phase was washed twice with 5%citric acid and brine. The organic phase was evaporated and the crudeproduct was dissolved in THF (25 mL). 1M LiOH solution in MeOH—H₂O(3:2v/v) (2.6 mL) was added and the mixture was stirred for 2h at roomtemperature. The reaction mixture was quenched with 5% citric acid andthe mixture was extracted with ethyl acetate (2×25mL). The organic layerwas washed with brine and dried over anhydrous Na₂SO₄. Solvent wasevaporated in vacuum and to afford the title compound which was pureenough to be used in the next step (1.6 g, yield 84%). TLC system: 20%EtOAc in pet ether, R_(f)=0.3.

Step j)2-(1-(tert-Butoxycarbonylamino)-3-fluorocyclobutyl)-2-hydroxyacetic Acid(BB3)

Compound BB3-i (1.6 g, 0.005 mol) was refluxed with 6N HCl (60 mL) for16 h until the amide hydrolysis was complete. The solvent was evaporatedunder reduced pressure and co-evaporated several times with water. Theproduct was dissolved in THF:H₂O (7:3 v/v, 50 mL), cooled to 0° C. andEt₃N (2.1 mL, 0.015 mol) was added followed by di-tert-butyl dicarbonate(2.18 g, 0.01 mol). The mixture was stirred at room temperatureovernight (pH was monitored in a regular interval and kept ˜11throughout the reaction). The reaction mixture was neutralized with 1NHCl and the product was extracted with EtOAc (2×50 mL). The organiclayer was washed with brine and dried over anhydrous Na₂SO₄ The solventwas evaporated under reduced pressure followed by purification by columnchromatography (silica gel 60-120 mesh, eluent 5% MeOH in CHCl₃) whichafforded the title P1 building block as a solid (0.65 g, yield 50%). TLCsystem: 30% MeOH in CHCl₃, R_(f)=0.3.

¹H NMR (400 MHz, d₆-DMSO) δ 7.01 (br s, 1H), 5.16 (br m, 1H), 4.97 (brm, 1H), 2.49 (br m, 5H), 1.36 (s, 9H); ms ES⁺ m/z 262 (100%).

Building Block 4—an Exemplary P1—Prime Side Building Block (BB4)

Step a) tert-butyl 1-(hydroxymethyl)-3-methoxycyclobutylcarbamate(BB4-a)

500 mg (1.51 mmol) of tert-butyl1-((tert-butyldimethylsilyloxy)methyl)-3-hydroxycyclobutylcarbamate(prepared by reduction ofethyl-1-[[(tert-butyloxy)carbonyl]amino]-3-hydroxycyclobutane-1-carboxylateas described in J. Med. Chem., 1990 33(10) 2905-2915) and proton sponge(N,N,N′,N′ tetramethylnapthalene-1,8 diamine) (1.63 g, 6.04 mmol) weredissolved in DCM (18 ml), cooled down to 0° C., (447 mg, 3.02 mmol) oftrimethyloxonium borontetrafluoride was added at once as a solid undervigorous stirring. The reaction mixture was stirred for 3h and dilutedwith DCM (50 ml) and 20 ml of brine, added under vigorous stirring. Theorganic phase was washed with sodium bicarbonate, brine, dried oversodium sulphate, evaporated and purified on short silica column (DCM asan eluent). The resulting product was dissolved in 5 ml of THF, 4.5 mlof 1M solution of tetrabutylammonium fluoride in THF (1M) was added,stirred at room temperature for 4.5 h. Monitored by TLC; evaporated withsilica, purified on silica (EtOAc-hexane 1:1 to neat EtOAc) which gavethe title compound (251 mg, 72%). LC/MS 232 (M+1).

Step b) tert-Butyl 1-formyl-3-methoxycyclobutylcarbamate (BB4-b)

Alcohol BB4-a was dissolved in 20 ml of DCM, Dess Martin periodinane wasadded at once. Stirred for 2.5 hours; diluted with 50 ml of DCM and 20ml of 10% Na2S2O3 was added, stirred, washed with sodium bicarbonate,brine, dried over sodium sulphate. Purified on silica (EtOAc-hexane 1:1to neat EtOAc) which gave the title compound (500 mg, 59%).

Step c) tert-Butyl1-(2-(cyclopropylamino)-1-hydroxy-2-oxoethyl)-3-methoxycyclobutylcarbamate(BB4)

Aldehyde BB4-b 498 mg (1.56 mmol) was dissolved in dry DCM (8 ml).Pyridine (0.52 ml) was added under stirring conditions, followed byadding cyclopropyl isonitrile. The reaction was placed in an ice-bathand 0.25 ml of TFA was added dropwise during 20 min. Reaction mixturewas stirred overnight. Washed with 1 M HCl, sodium bicarbonate, brine,dried over sodium sulphate, evaporated, dissolved in dioxane and stirredwith lithium hydroxide overnight and neutralized with citric acid. Theproduct was extracted with EtOAc from the resulting solution. Purifiedon silica (EtOAc-hexane 1:3 to 1:1) which gave 263 mg of the titlecompound (54%) LC/MS 314 (M+1).

Method A

EXAMPLE 1

Step a) Tert-butyl1-(1-hydroxy-2-(1-methyl-1H-pyrazol-3-ylamino)-2-oxoethyl)cyclobutylcarbamate(1-a)

1-Methyl-1H-pyrazol-3-amine (158 mg, 1.63 mmol) and DIEA (1.08 mL, 6.52mmol) was added to a solution of2-(1-(tert-butoxycarbonylamino)cyclobutyl)-2-hydroxyacetic acid (400 mg,1.63 mmol) dissolved in DMF (20 mL). The solution was cooled to 0° C.and after 10 minutes HATU (620 mg, 1.63 mmol) was added. Afterapproximately 2 hours at RT, LC-MS showed product and no startingmaterial and the solvent was removed by rotary evaporation. The crudeproduct was dissolved in 40 mL of EtOAc and washed with 25 mL of sat.NaHCO_(3(aq)). The organic phase was dried with Na₂SO₄, filtered andevaporated to dryness. The crude product was purified on a 25 g silicacolumn on a Biotage Flashmaster eluted with a gradient of heptane:ethylacetate 1:1, which gave the title compound as a white solid (488 mg,92%) yield. [M+H]⁺=325.

Step b) Tert-butyl(2S)-1-(1-(1-hydroxy-2-(1-methyl-1H-pyrazol-3-ylamino)-2-oxoethyl)cyclobutylamino)-3-(1-methylcyclobutyl)-1-oxopropan-2-ylcarbamate(1-b)

A pre made 9 to 1 mixture of methanol and acetyl chloride (10 mL) wasadded to compound 1-a (244 mg, 0.752 mmol) and the solution was stirredfor 6 hrs. The solvent was then removed by rotary evaporation and thecrude product put on high vacuum over night. The hydrochloride salt ofthe resultant unprotected P1-prime side building block was dissolved inDMF (15 mL) and(S)-2-(tert-butoxycarbonylamino)-3-(1-methylcyclobutyl)propanoic acid(193 mg, 7.52 mmol) and DIEA were added to the solution. The solutionwas cooled to 0° C. and after 10 minutes HATU (620 mg, 1.63 mmol) wasadded and the solution was allowed to reach RT. After approximately 2hours, the solvent was removed by rotary evaporation. The crude productwas dissolved in 40 mL of EtOAc and washed with 25 mL of sat.NaHCO_(3(aq)). The organic phase was dried with Na₂SO₄, filtered andevaporated to dryness. The crude product was purified on a 25 g silicacolumn eluted with a gradient of heptane:ethyl acetate, which gave thetitle compound (235 mg, 67%). [M+H]⁺=464.

Step c)N-((2S)-1-(1-(1-hydroxy-2-(1-methyl-1H-pyrazol-3-ylamino)-2-oxoethyl)-cyclobutylamino)-3-(1-methylcyclobutyl)-1-oxopropan-2-yl)-4-(phenylsulfonamido)-benzamide(1-c)

A pre made 9 to 1 mixture of methanol and acetyl chloride (8 mL) wasadded compound 1-b (100 mg, 0.216 mmol) and the solution was stirred for6 hrs. The solvent was then removed by rotary evaporation and the crudeproduct put under high vacuum over night. The hydrochloride salt of theresultant deprotected P2-P1-prime side unit was dissolved in DMF (15mL), 4-(phenylsulphonamido)benzoic acid (193 mg, 7.52 mmol) and DIEAwere added and the solution was cooled to 0° C. After 10 minutes HATU(620 mg, 1.63 mmol) was added and the solution was allowed to attain RT.After approximately 2 hours, the solvent was removed by rotaryevaporation, the crude product was dissolved in of EtOAc (40 mL) andwashed with sat. NaHCO_(3(aq)) (25 mL). The organic phase was dried withNa₂SO₄, filtered and evaporated to dryness. The crude product waspurified on a 25 g silica column on a Biotage Flashmaster eluted with agradient of DCM:methanol, which gave the title compound (112 mg, 83%).[M+H]⁺=623.

Step d)(S)-N-(1-(1-(2-(1-methyl-1H-pyrazol-3-ylamino)-2-oxoacetyl)cyclobutylamino)-3-(1-methylcyclobutyl)-1-oxopropan-2-yl)-4-phenylsulfonamido)benzamide(1)

Compound 1-c (112 mg, 0.180 mmol) was dissolved in dichloromethane (15mL) and Dess Martin periodinane (114 mg, 0.270 mmol) was added to thesolution. The cloudy reaction mixture was stirred for 4 hours.Thereafter 10% Na₂S₂O_(3(aq)) (15 mL) and 10% NaHCO_(3(aq)) (15 mL) wereadded and the solution was stirred until it became clear. The organicphase was separated from the aqueous one by a phase separator. Theorganic solvent was removed by rotary evaporation and the crude productwas dissolved in a small amount of acetonitrile and H₂O for purificationon a semi-preparative LC-MS. The purification was done on a XBridgephenyl 5 μm column using mobile phase A (90:10 H₂O: acetonitrile, 10 mMNH₄Ac) and B (10:90 H₂O: acetonitrile, 10 mM NH₄Ac) going from 35-50% B.The title product was purified and by freeze dried, as a white solid in28% yield (31 mg). [M+H]⁺=621. ¹H NMR (CDCl₃, 400 MHz) 1.15 (s, 3H),1.48-2.17 (m, 10 H), 2.19-2.37 (m, 2H), 2.70 (bs, 1H), 2.83 (bs, 1H),3.69 (s, 3H), 4.89 (m, 1H), 6.42 (s, 1H), 7.06 (s, 1H), 7.10-7.57 (m, 9H), 7.81-7.97 (m, 3H), 9.27 (bs, 1H), 9.53 (bs, 1H).

EXAMPLES 2-49

The compounds illustrated in the tables below were prepared analogouslyto the procedure outlined in Example 1 using the appropriateR^(1a)R^(1b) amines and P1, P2 and P3 building blocks, followed by DessMartin oxidation to the end product α-keto amide.

TABLE 1

Ex. R⁴ R³ R^(1b) M/Z  2¹ morpholin-4-yl 1-methylcyclopentyl- cyclopropyl449 [M + 1] methyl  2¹ morpholin-4-yl 1-methylcyclopentyl- cyclopropyl449 [M + 1] methyl  3¹ morpholin-4-yl 1-methylcyclopentyl- cyclobutyl461.3 [M − 1] methyl 374.2 [M − 88]  4¹ morpholin-4-yl1-methylcyclopentyl- methyl [M + H]⁺ = 423.3 methyl [2M + Na]⁺ = 867.4[M − H]⁻ = 421.1  5¹ morpholin-4-yl 1-methylcyclopentyl- CH₂CHF₃ 489.1[M − 1] methyl 402.2 [M − 88]  6¹ morpholin-4-yl 1-methylcyclopentyl-1-methyl-pyrazol-3-yl 487.3 [M − 1] methyl  7 fur-3-yl1-methylcyclopentyl- cyclopropyl 452 [M + Na] methyl  8 fur-3-yl1-methylcyclopentyl- cyclobutyl 442.2 [M − 1] methyl 345.1 [M − 98]  9fur-3-yl 1-methylcyclopentyl- methyl [M + H]⁺ = 404.2 methyl [M + Na]⁺ =426.2 [2M + Na]⁺ = 830.3 [M − H]⁻ =402.1 10 fur-3-yl1-methylcyclopentyl- CH₂CHF₃ 470.1 [M − 1] methyl 11 fur-3-yl1-methylcyclopentyl- 1-methyl-pyrazol-3-yl 470.1 [M + 1] methyl 12 4-1-methylcyclopentyl- cyclopropyl 595.1 [M + H] phenylsulphonamido methylphenyl 13 4-benzenesulphonyl- 1-methylcyclopentyl- 1-methyl-pyrazol-3-yl653.3 [M + H] aminophen-1-yl methyl 14 4-fluorophen-1-yl1-methylcyclopentyl- cyclopropyl 456.2 [M − 1] methyl 373.2 [M − 84] 154-benzenesulphonyl- cyclohexylmethyl cyclopropyl aminophen-1-yl 16benzofuran-2-yl 1-methylcyclopentyl- cyclopropyl 480.2 [M + 1] methyl478.4 [M − 1] 17 fur-2-yl 1-methylcyclopentyl- cyclopropyl 428.1 [M − 1]methyl 345.2 [M − 84] 18 pyrazin-2-yl 1-methylcyclopentyl- cyclopropyl440.1 [M − 1] methyl 19 1,3-dimethylpyrazol- 1-methylcyclopentyl-cyclopropyl 456.2 [M − 1] 5-yl methyl 20¹ morpholin-4-yl homo-t-butylcyclopropyl 423.2 [M + 1] 21 fur-3-yl homo-t-butyl cyclopropyl 402.1 [M− 1] 319.2 [M − 84] 22 fur-3-yl cycloheptylmethyl cyclopropyl 442.1 [M −1] ¹Morpholine carbonylchloride was used to introduce the P3-buildingblock in step d.

TABLE 2

Ex. R⁴ R³ MS 23 fur-3-yl homo-t-butyl 440 [M + 1] 24 fur-3-yl1-methyl-cyclobutylmethyl 25 fur-3-yl 2-methyl,2-fluoroprop-1-yl 26fur-3-yl cyclohexylmethyl 27 fur-3-yl 1-methyl-cyclopentylmethyl 466[M + 1] 28¹ morpholin-4-yl homo-t-butyl 459 [M + 1] 29¹ morpholin-4-yl1-methyl-cyclobutylmethyl 471 [M + 1] 30¹ morpholin-4-yl2-methyl,2-fluoroprop-1-yl 463.2 [M + H] 31¹ morpholin-4-ylcyclohexylmethyl 32¹ morpholin-4-yl 1-methyl-cyclopentylmethyl 485 [M +1] 33 4-benzenesulphonyl- 1-methyl-cyclopentylmethyl aminophen-1-yl¹Morpholine carbonylchloride was used to introduce the P3-building blockin step d.

TABLE 3

Ex. R⁴ R^(1b) R^(1a) M/Z 34¹ morpholin-4-yl methyl methyl 437 [M + 1]35¹ morpholin-4-yl 3-chloropropyl H 485.2 [M + 1] 36¹ morpholin-4-ylcyclopropyl methyl [M + H]⁺ = 463.3 [M + Na]⁺ = 485.2 [2M + Na]⁺ =948.4.3 [M − H]⁻ = 461.2 37¹ morpholin-4-yl isopropyl H 451 (M + 1] 38¹morpholin-4-yl benzyl H 499.2 [M + 1] 497.4 [M − 1] 39¹ morpholin-4-ylpyridin-3- H 500.1 [M + H] ylmethyl 40¹ morpholin-4-yl methyl H 423.3[M + H] 41 fur-3-yl chlorocyclopropyl H 464.1 [M − 1] 42 fur-3-ylcyclopropyl methyl [M + H]⁺ = 444.3 [M + Na]⁺ = 466.1 [2M + Na]⁺ = 909.4[M − H]⁻ = 442.1 43 fur-3-yl isopropyl H 432 [M + 1] 44 fur-3-yl benzylH 478.1 [M − 1] 45 fur-3-yl methyl H 481.1 [M + H] ¹Morpholinecarbonylchloride was used to introduce the P3-building block in step d.

TABLE 4

Ex R⁴ R³ R^(2a) R^(2b) R^(1b) M/Z 46¹ morpholin-4-yl1-methylcyclopentylmethyl H F cyclopropyl 467.2 [M + 1] 465.3 [M − 1]579.1 [M + 113] 47¹ morpholin-4-yl 1-methylcyclopentylmethyl OMe² Hcyclopropyl 464.2 [M + H] 462.1 [M − 1] 48 furan-3-yl1-methylcyclopentylmethyl Cl H cyclopropyl 464.2 [M + 1] 462.1 [M − 1]49 furan-3-yl 1-methylcyclopentylmethyl OMe² H cyclopropyl 50¹morpholin-4-yl 1-methylcyclobutylmethyl H H methyl 409.3 [M + H]⁺¹Morpholine carbonylchloride was used to introduce the P3-building blockin step d. ²The stereochemistry at the chiral centre to which R^(2a) &R^(2b) are attached is not determined.

Method B

EXAMPLE 50

Step a)[1-(Cyclopropylcarbamoyl-hydroxy-methyl)-3,3-difluoro-cyclobutyl]-carbamicAcid tert-butyl Ester (50-a)

Cyclopropylamine (1 eq, 1.63 mmol) and DIEA (4 eq, 6.52 mmol) was addedto a solution of BB2 (1 eq, 1.63 mmol) dissolved in DMF (˜8 ml/mmol).The solution was cooled to 0° C. and after 10 minutes HATU (1 eq, 1.63mmol) was added. After approximately 2 hours at RT, LC-MS showed productand no starting material and the solvent was removed by rotaryevaporation. The crude product was dissolved in 40 mL EtOAc and washedwith 25 mL sat. NaHCO_(3(aq)). The organic phase was dried with Na₂SO₄,filtered and evaporated to dryness. The crude product was purified on a25 g silica column on a Biotage Flashmaster, which gave the titleproduct as a white solid (92%).

Step b)[1-{1-[Hydroxy-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-methyl]-cyclobutylcarbamoyl}-2-(1-methyl-cyclopentyl)-ethyl]-carbamicAcid tert-butyl Ester (50-b)

Compound 50-a (50 mg, 0.156 mmol) was dissolved in a solution ofmethanol:acetyl chloride 9:1 (1.5 mL) at 0° C. The solution was stirredat RT for 16 h, then concentrated and co-evaporated twice with DCM. Theafforded residue was dissolved in anhydrous DMF (1 mL) and then added at0° C. to a cold solution of(S)-2-(tert-butoxycarbonylamino)-3-(1-fluorocyclopentyl)propanoic acid(prepared as described in Ex. 8 of WO2006/064286) (45 mg, 0.165 mmol)and HATU (63 mg, 0.165 mmol) in dry DMF (2 mL). DIEA (130 μL, 0.75 mmol)was added, and the reaction mixture was stirred at 0° C. for 30 minutes,then at RT for 2 h. The solution was concentrated under vacuum, theresidue was dissolved in DCM (3 mL) and applied to a silica column (10g). The compound was purified by flash chromatography (heptane: ethylacetate 75:25-25:75) which gave the title compound (74 mg, 95%) as amixture of diastereomers. MS m/z 478.2 (M+H)⁺.

Step c)[1-(1-Cyclopropylaminooxalyl-3,3-difluoro-cyclobutylcarbamoyl)-2-(1-fluoro-cyclopentyl)-ethyl]-carbamicAcid tert-butyl Ester (50-c)

The α-hydroxy amide 50-b was oxidized according to the method describedin Example 1 step d. Purification by flash chromatography, which gavethe title compound as a mixture of diastereomers. MS m/z 476.2 [M+H]⁺.

Step d)N-[1-(1-Cyclopropylaminooxalyl-3,3-difluoro-cyclobutylcarbamoyl)-2-(1-fluoro-cyclopentyl)-ethyl]-3-fluoro-4-hydroxy-benzamide(50)

Carbamate 50-c (71 mg, 0.15 mmol) was dissolved in a solution ofmethanol:acetyl chloride 9:1 (1.5 mL) at 0° C. The solution was stirredat room temperature for 16 hrs, then concentrated and co-evaporatedtwice with DCM. The crude product was dissolved in dry DMF (1 mL) at 0°C. and then added to a cold solution of 4-hydroxy-3-fluorobenzoic acid(25 mg, 0.165 mmol) and HATU (63 mg, 0.165 mmol) in dry DMF (2 mL). DIEA(130 μL, 0.75 mmol) was added and the reaction mixture was stirred at 0°C. for 30 minutes, then at RT for 2 h. The solution was concentratedunder vacuum and the residue was dissolved in DCM (3 mL) and purified byflash chromatography on a silica column (10 g) eluted with (DCM:MeOH100:0-92:8) and then by prep (20-70% gradient, mobile phase:acetonitrile-water, 1% NH₄OH), which gave the title compound (4.2 mg,6%). MS m/z 514.1 494 (M−HF)⁺. Purity 91% as assessed by analyticalLCMS.

The compounds illustrated in the table below were prepared analogouslyto the procedure outlined in either of method A or B using theappropriate R^(1a)R^(1b) amines, P1 and P2-building blocks and P3 acids.

TABLE 5

Ex. Method R⁴ R³ R^(2a) R^(2b) R^(1b) [M + H]⁺  51 A¹ morpholin-4-yl1-methylcyclobutyl- H H methyl 409.3 methyl  52 B 3-fluoro-4-1-fluorocyclopentyl- H H cyclopropyl 478.2 hydroxybenzyl methyl  53A^(1,2) morpholin-4-yl 1-methylcyclopentyl- F H cyclopropyl 467.2 methyl 54 B³ cyclopropyl 1-methylcyclopentyl- F F 1-methylpyrazol-3-yl 480.3methyl  55 A 2-pyrazinyl 1-methylcyclopentyl- F F 1-methylpyrazol-3-yl504.2 methyl  56 A thiazol-5-yl 1-methylcyclopentyl- F F1-methylpyrazol-3-yl 509.1 methyl  57 B³ 3-fluoro-4- (1- F⁴ Hcyclopropyl 506.2 methoxyphenyl methylcyclopentyl)- methyl  58 B⁵4-fluorophenyl (1- F F cyclopropyl 494.2 methylcyclopentyl)- methyl  59A^(2,6,7,8) thiazol-5-yl (1- H H 1-methylimidazol-4- 487.3methylcyclopentyl)- yl methyl  60 A^(2,5,8) cyclopropyl1-methylcyclopentyl- F H 1-methylpyrazol-3-yl 462.2 methyl  61 A⁵cyclopropyl 1-fluorocyclopentyl- F H 1-methylpyrazol-3-yl 466.06 methyl 62 A¹ morpholin-4-yl neopentyl F H 1-(2,2,2-trifluoro- 549.2ethyl)-pyrazol-3-yl  63 A² 3-imidazol- 1-methylcyclopentyl- H H1-methylpyrazol-3-yl 546.3 benzyl methyl  64 A furan-3-ylmethylcyclohexyl H H cyclopropyl 430  65 A 4′-(methyl-1-methylcyclobutyl- H H cyclopropyl 580 sulfonyl)biphen- methyl yl-4-yl 66 A 4′-(methyl- 1-methylcyclopentyl- H H cyclopropyl 594sulfonyl)biphen- methyl yl-4-yl  67 A morpholin-4-yl methylcyclohexyl HH cyclopropyl 449  68 A 4′-(methyl- neopentyl H H cyclopropyl 568sulfonyl)biphen- yl-4-yl  69 A furan-3-yl 1-methylcyclopentyl- H Hpyridin-4-yl-methyl 481 methyl  70 A furan-3-yl 1-methylcyclopentyl- H H3-methylbutan-2-yl 460 methyl  71 A furan-3-yl 1-methylcyclobutyl- H Hcyclopropyl 416 methyl  72 A morpholin-4-yl 1-methylcyclobutyl- H Hcyclopropyl 435 methyl  73 A furan-3-yl 1-methylcyclobutyl- H H methyl390 methyl  74 A morpholin-4-yl 1-methylcyclopentyl- H H3-methylbutan-2-yl 479 methyl  75 A 4- neopentyl H H methyl 543phenylsulphon- amidophenyl  76 A furan-3-yl 1-methylcyclopentyl- H H3-chloropropyl 466 methyl  77 A 4-(4-chloro- 1-methylcyclopentyl- H H4-(4-chlorophenyl- 630 phenylsulphon- methyl sulfonamido)phenylamido)-phenyl  78 A 4- neopentyl H H cyclopropyl na phenylsulphon-amidophenyl  79 A morpholin-4-yl 1-methylcyclopentyl- H H4-pyridylmethyl 500 methyl  80 A 4- 1-methylcyclobutyl- H H methyl 555phenylsulphon- methyl amidophenyl  81 B³ 3-fluoro-4- 1-methylcyclobutyl-H H cyclopropyl 460 hydroxyphenyl methyl  82 A 4-(2,4-dimethyl-1-methylcyclopentyl- H H cyclopropyl 630 thiazol-5- methyl sulfonamido)-phenyl  83 A 4-fluorophenyl methylcyclohexyl H H cyclopropyl 458  84 A4-(pyridine-3- 1-methylcyclopentyl- H H cyclopropyl 596 sulfonamido)-methyl phenyl  85 A 3-fluoro-4- 1-methylcyclopentyl- H H cyclopropyl 474hydroxyphenyl methyl  86 A 2-fluoro-4- 1-methylcyclobutyl- H Hcyclopropyl 460 hydroxyphenyl methyl  87 A 2-oxo-1,2,3,4-1-methylcyclopentyl- H H cyclopropyl 510 tetrahydro- methylquinazolin-6-yl  88 A 2-fluoro-4- 1-methylcyclopentyl- H H cyclopropyl474 hydroxyphenyl methyl  89 A 4-(pyridine-3- 1-methylcyclobutyl- F H1-methylpyrazol-3-yl 640 sulfonamido)- methyl phenyl  90 A 4-1-methylcyclopentyl- H H cyclopropyl 456 hydroxyphenyl methyl  91 A3-methyl-2-oxo- 1-methylcyclopentyl- H H cyclopropyl 1,2,3,4- methyltetrahydro- quinazolin-6-yl  92 A morpholin-4-yl 1-methylcyclopentyl- HH 1,5-dimethylpyrazol- 503 methyl 3-yl  93 A morpholin-4-yl1-methylcyclopentyl- H H 1,4-dimethylpyrazol- 503 methyl 3-yl  94 Apyrrol-3-yl 1-methylcyclopentyl- H H cyclopropyl 429 methyl  95 Abenzofuran-2-yl 1-methylcyclopentyl- H H t.butyl 496.3 methyl  96 Afuran-2-yl 1-methylcyclopentyl- H H t.butyl 446.2 methyl  97 Amorpholin-4-yl 1-methylcyclopentyl- H H 2-morpholinoethyl 522.2 methyl 98 A furan-2-yl 1-methylcyclopentyl- H H 2-morpholinoethyl 503.2 methyl 99 A furan-2-yl 1-methylcyclopentyl- H H 3-pyridinemethyl 481.3 methyl100 A 4-(phenylsulfon- 1-methylcyclobutyl- H H 1-methylpyrazol-3-yl621.3 amido)phenyl methyl 101 A phenyl- 1-methylcyclobutyl- H H1-methylpyrazol-3-yl 506.2 cyclopropyl methyl 102 A pyrazin-2-yl1-methylcyclobutyl- F H 1-methylpyrazol-3-yl 486.3 methyl 103 Amorpholin-4-yl 1-methylcyclopentyl- H H 1-cyclopropyl- 529.3 methylmethylpyrazol-3-yl 104 A morpholin-4-yl 1-methylcyclopentyl- H H1-benzylpyrazol-3-yl 565.3 methyl 105 A thiazol-5-yl1-methylcyclopentyl- H H 1-cycloprpoyl- n.a. methyl methylpyrazol-3-yl106 A morpholin-4-yl 1-methylcyclopentyl- H H 1-(2,2-difluoroethyl)-539.2 methyl pyrazol-3-yl 107 A morpholin-4-yl 1-methylcyclopentyl- H H1-(2,2,2trifluoro- 557.3 methyl ethyl)pyrazol-3-yl 108 A thiazol-5-yl1-methylcyclobutyl- F H 1-methylpyrazol-3-yl 491.2 methyl 109 Amorpholin-4-yl 1-methylcyclobutyl- F F 1-methylpyrazol-3-yl n.a. methyl110 A morpholin-4-yl 1-methylcyclobutyl- F H 1-methylpyrazol-3-yl 493.3methyl 111 A morpholin-4-yl cyclohexyl F F 1-methylpyrazol-3-yl 525.3112 A morpholin-4-yl neopentyl F H 1-methylpyrazol-3-yl 481.3 113 B3-fluoro-4- cyclohexyl F F 1-methylpyrazol-3-yl 467.2 hydroxyphenyl 114B 3-fluoro-4- 4,4-difluoro- F F 1-methylpyrazol-3-yl n.a. hydroxyphenylcyclohexyl 115 B⁹ 3-chloro-4- 1-methylcyclopentyl- F F1-methylpyrazol-3-yl 566.2 hydroxyphenyl methyl 116 B⁹ 3-fluoro-4-1-methylcyclopentyl- F F 1-methylpyrazol-3-yl 550.2 hydroxyphenyl methyl117 B⁹ 3-chloro-4- cyclohexyl F F 1-methylpyrazol-3-yl 566.2hydroxyphenyl 118 B⁹ 3-fluoro-4- 1-methylcyclobutyl- F F1-methylpyrazol-3-yl 536.2 hydroxyphenyl methyl 119 B⁹ 3-fluoro-4-neopentyl F F 1-methylpyrazol-3-yl 524.2 hydroxyphenyl 120 B⁹3-fluoro-4- 1-methylcyclopentyl- OMe¹⁰ H cyclopropyl 504.3 hydroxyphenylmethyl 121 A 4-(phenylsulfon- 1-methylcyclopentyl- F F cyclopropyl n.a.amido)phenyl methyl 122 A¹ morpholin-4-yl 1-methylcyclobutyl- OMe¹⁰ Hcyclopropyl n.a. methyl ¹Morpholine carbonylchloride was used tointroduce the P3-building block in step d of method A. ²PyBop was usedas coupling agent in step b of Method A. ³The Boc group was removedusing 4M HCl-dioxane in step d of Method B. ⁴F is trans to NH. ⁵The P3moiety was introduced by coupling with the corresponding acid chloride.⁶The R^(1a)R^(1b)-amine was achieved by reduction of the correspondingnitro comnpound. ⁷PyBop was used as coupling agent in step a of MethodA. ⁸The Boc group was removed using TFA/water/triisopropylsilane9.5:0.5:0.5 in step c of Method A. ⁹The tert-butyldiphenylsilyl hydroxyprotected derivative of the P3 acid was used in the step d of Method B.The target compound was achieved desilylation effected by treatment withTBAF in THF. ¹⁰The stereochemistry at the chiral centre to which R^(2a)& R^(2b) are attached is not determined.

EXAMPLE 123

2-Amino-3-(1-methyl-cyclopentyl)-propionic Acid Methyl EsterxHCl (123-a)

(S)-2-(tert-Butoxycarbonylamino)-3-(1-methylcyclopentyl)propanoic acid,(272 mg, 1 mmol) was dissolved in MeOH (1 mL). 4M HCl in dioxane wasadded dropwise (3 mL) at room temperature. After approximately 3 hours,the solvent was removed by rotary evaporation and the residue wasco-evaporated with MeOH (2×) to remove excess HCl. The afforded compoundwas used in subsequent steps without further purification.

Step b)3-(1-Methyl-cyclopentyl)-2-[(pyrrolidine-1-carbonyl)-amino]-propionicAcid Lithium Salt, (123-b)

Compound 123-a (19 mg, 86 μmol) was dissolved in THF (1 mL) andtriethylamine (3 eq) and pyrrolidine-1-carbonyl chloride (1 eq) wasadded. The reaction was heated to 50° C. in a sealed tube for 16 h.LC/MS analysis showed 90% conversion. EtOAc was added to the reactionsolution and the organic phase was washed with 0.1M HCl (aq) (3×). Theorganic layer was dried (MgSO₄), filtered and the solvent removed invacuo. The resulting crude methylester was dissolved in THF, and 1M LiOHin methanol (3 eq) was added. The solution stirred at room temperaturefor 16 h. LC/MS analysis indicated complete ester hydrolysis and thesolvent was removed in vacuo to afford the lithium salt that was used insubsequent step without further purification.

Step c) Pyrrolidine-1-carboxylic Acid[1-[3-fluoro-1-(1-methyl-1H-pyrazol-3-ylaminooxalyl)-cyclobutylcarbamoyl]-2-(1-methyl-cyclopentyl)-ethyl]-amide(123)

The TFA salt of2-(1-Amino-3-fluorocyclobutyl)-2-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)acetamide(64 μmol) was dissolved in DCM (2 mL) and added to a solution of 123-b(1.2 eq) PyB OP (1.2 eq) in DCM (2 mL) that had been pre-stirred at roomtemperature for 10 min. The mixture was stirred at room temperature for16 h and then DCM was added to the reaction and the organic phase waswashed with 0.1 M HCl (aq) (2×) and 10% NaHCO₃ (aq) (233 ). The organicphase was dried and concentrated in vacuo and the residue purified bypreparative LC/MS. The afforded alcohol was re-dissolved in DCM (1.5 mL)and Dess Martin periodinane (1.5 eq μmol) was added in one portion atroom temperature. The reaction was stirred at room temperature for 2 hafter which time LC/MS analysis indicated complete oxidation. Thereaction was diluted with DCM and the solution washed with a 1:1 mixtureof 10% Na₂S₂O₃ (aq) and 10% NaHCO₃ (aq). The organic layer was elutedthrough a hydrophobic Phase Separator and concentrated in vacuo. Theresidue was purified by preparative LC/MS to afford the target compound.(Yield: 5.1 mg, LC/MS: t_(R)=4.97 min, 491.14 [M+H]⁺).

BIOLOGICAL EXAMPLES

Determination of Cathepsin K Proteolytic Catalytic Activity

Convenient assays for cathepsin K are carried out using humanrecombinant enzyme, such as that described in PDB.

ID BC016058 standard; mRNA; HUM; 1699 BP.

DE Homo sapiens cathepsin K (pycnodysostosis), mRNA (cDNA cloneMGC:23107

RX MEDLINE;. RX PUBMED; 12477932.

DR RZPD; IRALp962G1234.

DR SWISS-PROT; P43235;

The recombinant cathepsin K can be expressed in a variety ofcommercially available expression systems including E coli, Pichia andBaculovirus systems. The purified enzyme is activated by removal of theprosequence by conventional methods.

Standard assay conditions for the determination of kinetic constantsused a fluorogenic peptide substrate, typically H-D-Ala-Leu-Lys-AMC, andwere determined in either 100 mM Mes/Tris, pH 7.0 containing 1 mM EDTAand 10 mM 2-mercaptoethanol or 100 mMNa phosphate, imM EDTA, 0.1%PEG4000 pH 6.5 or 100 mM Na acetate, pH 5.5 containing 5 mM EDTA and 20mM cysteine, in each case optionally with 1M DTT as stabiliser. Theenzyme concentration used was 5 nM. The stock substrate solution wasprepared at 10 mM in DMSO. Screens were carried out at a fixed substrateconcentration of 60 μM and detailed kinetic studies with doublingdilutions of substrate from 250 μM. The total DMSO concentration in theassay was kept below 3%. All assays were conducted at ambienttemperature. Product fluorescence (excitation at 390 nm, emission at 460nm) was monitored with a Labsystems Fluoroskan Ascent fluorescent platereader. Product progress curves were generated over 15 minutes followinggeneration of AMC product.

Cathepsin S Ki Determination

The assay uses baculovirus-expressed human cathepsin S and theboc-Val-Leu-Lys-AMC fluorescent substrate available from Bachem in a 384well plate format, in which 7 test compounds can be tested in parallelwith a positive control comprising a known cathepsin S inhibitorcomparator.

Substrate Dilutions

280 μl/well of 12.5% DMSO are added to rows B-H of two columns of a 96deep well polypropylene plate. 70 μl/well of substrate is added to rowA. 2×250 μl/well of assay buffer (100 mM Na phosphate, 100 mM NaCl, pH6.5) is added to row A, mixed, and double diluted down the plate to rowH.

Inhibitor Dilutions

100 μl/well of assay buffer is added to columns 2-5 and 7-12 of 4 rowsof a 96 well V bottom polypropylene plate. 200 μl/well of assay bufferis added to columns 1 and 6.

The first test compound prepared in DMSO is added to column 1 of the toprow, typically at a volume to provide between 10 and 30 times theinitially determined rough K_(i). The rough Ki is calculated from apreliminary run in which 10 μl/well of 1 mM boc-VLK-AMC ( 1/10 dilutionof 10 mM stock in DMSO diluted into assay buffer) is dispensed to rows Bto H and 20 μ/well to row A of a 96 well Microfluor™ plate. 2 μl of each10 mM test compound is added to a separate well on row A, columns 1-10.Add 90 μl assay buffer containing 1 mM DTT and 2 nM cathepsin S to eachwell of rows B-H and 180 μl to row A. Mix row A using a multichannelpipette and double dilute to row G. Mix row H and read in thefluorescent spectrophotometer. The readings are Prism data fitted to thecompetitive inhibition equation, setting S=100 μM and K_(M)=100 μM toobtain an estimate of the K_(i), up to a maximum of 100 μM.

The second test compound is added to column 6 of the top row, the thirdto column 1 of the second row etc. Add 1 μl of comparator to column 6 ofthe bottom row. Mix column 1 and double dilute to column 5. Mix column 6and double dilute to column 10.

Using an 8-channel multistepping pipette set to 5×10 μl, distribute 10μl/well of substrate to the 384 well assay plate. Distribute the firstcolumn of the substrate dilution plate to all columns of the assay platestarting at row A. The tip spacing of the multichannel pipette willcorrectly skip alternate rows. Distribute the second column to allcolumns starting at row B.

Using a 12-channel multistepping pipette set to 4×10 μl, distribute 10μ/well of inhibitor to the 384 well assay plate. Distribute the firstrow of the inhibitor dilution plate to alternate rows of the assay platestarting at A1. The tip spacing of the multichannel pipette willcorrectly skip alternate columns. Similarly, distribute the second,third and fourth rows to alternate rows and columns starting at A2, B1and B2 respectively.

Mix 20 ml assay buffer and 20 μl 1M DTT. Add sufficient cathepsin S togive 2 nM final concentration.

Using the a distributor such as a Multidrop 384, add 30 μl/well to allwells of the assay plate and read in fluorescent spectrophotomoter suchas an Ascent.

Fluorescent readings, (excitation and emission wavelengths 390 nm and460 nm respectively, set using bandpass filters) reflecting the extentof enzyme cleavage of the fluorescent substrate, notwithstanding theinhibitor, are linear rate fitted for each well.

Fitted rates for all wells for each inhibitor are fitted to thecompetitive inhibition equation using SigmaPlot 2000 to determine V, Kmand Ki values.

Cathepsin L Ki

The procedure above with the following amendments is used for thedetermination of Ki for cathepsin L.

The enzyme is commercially available human cathepsin L (for exampleCalbiochem). The substrate is H-D-Val-Leu-Lys-AMC available from Bahcem.The assay buffer is 100 mM sodium acetate 1 mM EDTA, pH5.5) The DMSOstock (10 mM in 100% DMSO) is diluted to 10% in assay buffer. Enzyme isprepared at 5 nM concentration in assay buffer plus 1 mM dithiothreitoljust before use. 2 ul of 10 mM inhibitor made up in 100% DMSO isdispensed into row A. 10 μl of 50 μM substrate (= 1/200 dilution of 10mM stock in DMSO, diluted in assay buffer).

Inhibition Studies

Potential inhibitors are screened using the above assay with variableconcentrations of test compound. Reactions were initiated by addition ofenzyme to buffered solutions of substrate and inhibitor. K_(i) valueswere calculated according to equation 1.

$\begin{matrix}{v_{0} = \frac{VS}{{K_{M}\left( {1 + \frac{I}{K_{i}}} \right)} + S}} & (1)\end{matrix}$

where v₀ is the velocity of the reaction, V is the maximal velocity, Sis the concentration of substrate with Michaelis constant of K_(M), andI is the concentration of inhibitor. The inhibition of cathepsin S,cathepsin K and Cathepsin L exhibited by a selection of the compounds ofthe invention represented as Ki values expressed in nanomolar, ispresented in the table below.

TABLE 1 Example Ki Cat. S Ki Cat. K Ki Cat. L 2 2.3 3500 7100 6 0.19 460600 27 0.79 2300 12000 35 2 3500 6300 45 0.75 1100 7000 50 1 2400 310052 0.75 1400 1000 60 0.24 360 1700 75 0.59 310 14000 111 0.65 3600 200122 3.9 1000 3800 123 0.35 180 1500

The compounds of formula II are thus potent inhibitors of cathepsin Sand yet selective over the closely related cathepsin K and L.

All references referred to in this application, including patent andpatent applications, are incorporated herein by reference to the fullestextent possible.

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer, step, group of integers or group of steps but notto the exclusion of any other integer, step, group of integers or groupof steps.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims:

1. A compound of the formula I:

wherein R^(1a) is H; and R^(1b) is C₁-C₆ alkyl, optionally substituted with 1-3 substituents independently selected from: halo, hydroxy, cyano, azido, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy, C₁-C₄alkoxycarbonyl, C₁-C₄alkylcarbonyl, amine, C₁-C₄alkylamine, C₁-C₄-dialkylamine, C₁-C₄alkylsulfonyl, C₁-C₄alkylsulfonylamino, aminocarbonyl, aminosulphonyl, Carbocyclyl and Het; or R^(1b) is Carbocyclyl or Het; or R^(1a) and R^(1b) together with the N atom to which they are attached define a saturated cyclic amine with 3-6 ring atoms; wherein the Carbocyclyl, Het or cyclic amine is optionally substituted with 1-3 substituents independently selected from halo, hydroxy, cyano, azido, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy, C₁-C₄alkoxycarbonyl, C₁-C₄alkylcarbonyl, amino, C₁-C₄alkylamino, C₁-C₄dialkylamino, C₁-C₄alkylsulfonyl, C₁-C₄alkylsulfonylamino, aminocarbonyl, aminosulphonyl, RxOC(═O)-C₀-C₂alkylenyl (where Rx is H, C₁-C₄alkyl or C₁-C₄haloalkyl), phenyl, benzyl or C₃-C₆cycloalkyl-C₀-C₂alkylenyl; wherein the phenyl, benzyl or cycloalkyl moiety is optionally substituted with 1-3 substituents independently selected from halo, C₁-C₄alkyl, C₁-C₄haloalkyl or C₁-C₄alkoxy; R^(2a) and R^(2b) are independently selected from H, halo, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy; or R^(2a) and R^(2b) together with the carbon atom to which they are attached form a C₃-C₆cycloalkyl; R³ is a C₅-C₁₀alkyl, optionally substituted with 1-3 substituents independently selected from halo, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy; or R³ is a C₂-C₄alkyl chain with at least 2 chloro or 3 fluoro substituents; or R³ is C₃-C₇cycloalkylmethyl, optionally substituted with 1-3 substituents selected from C₁-C₄alkyl, halo, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₁-C₄haloalkoxy; R⁴ is Het or Carbocyclyl, either of which is optionally substituted with 1-3 substituents independently selected from: halo, azido, cyano, hydroxy, oxo, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy, C₁-C₄alkoxycarbonyl, C₁-C₄alkylcarbonyl, C₁-C₄alkylsulfonyl, C₁-C₄alkylsulfonylamino, aminosulphonyl, —NRkRl, —C(═O)NRkRl, —NRkC(═O)Rl, —NRkC(═O)ORl, —NRk(C═O)NRkRl, wherein oxo as substituent may be present only where valence so permits, where Rk and Rl are independently H, C₁-C₄ alkyl, or one is H and the other is —C(═O)C₁-C₄alkyl; and/or wherein in the Het or Carbocyclyl group is optionally substituted with a group of the formula —X—R5; wherein X is C₁-C₄alkylene or a 1-4 membered linkage comprising 0-3 methylene groups disposed adjacent to, or on either side of a CH(CH₃), C(CH₃)₂, CF₂, ethene, ethyne, C₀-C₄alkylamino, C₀-C₄alkylamido, sulphonamido, aminosulphonyl, ester, ether, urea or carbamate function; R⁵ is H, C₁-C₄alkyl or a monocyclic ring selected from C₃-C₆cycloalkyl, C₃-C₆cycloalkenyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrazolyl, pyrazolyl, indolyl, the C₁-C₄alkyl or monocyclic ring being optionally substituted with one to three substituents selected from: halo, azido, cyano, hydroxy, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy, C₁-C₄alkoxycarbonyl, C₁-C₄alkylcarbonyl, amino, C₁-C₄alkylamino, C₁-C₄-dialkylamino, C₁-C₄alkylsulfonyl, C₁-C₄alkylsulfonylamino, aminocarbonyl, aminosulphonyl; Het is a stable, monocyclic or bicyclic, saturated, partially saturated or aromatic ring system, containing 1-4 hetero atoms independently selected from O, S and N, and each ring having 5 or 6 ring atoms; Carbocyclyl is C₃-C₆cycloalkyl, C₅-C₆cycloalkenyl or phenyl; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof.
 2. A compound according to claim 1, wherein R^(1b) is methyl, cyclopropyl, 1-phenethyl, or a 5 or 6 membered heterocyclic ring containing 1-3 nitrogen atoms and 0 or 1 sulphur atoms, the cyclopropyl, phenyl or heterocyclic ring being optionally substituted with up to three substituents independently selected from C₁-C₄alkyl, halo, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy, C₁-C₄alkoxycarbonyl, C₁-C₄alkylcarbonyl, amino, C₁-C₄alkylamine, C₁-C₄dialkylamine, C₁-C₄alkylsulfonyl, C₁-C₄alkylsulfonylamino, aminocarbonyl, aminosulphonyl, RxOC(═O)—C₀-C₂alkylene (where Rx is H or C₁-C₄alkyl) or C₃-C₆cycloalkylC₀-C₂alkylene or benzyl (the cycloalkyl or benzyl being optionally substituted with 1-3 substituents selected from C₁-C₄alkyl, halo, C₁-C₄haloalkyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy)
 3. A compound according to claim 2, wherein the heterocyclic ring is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, or thiadiazolyl, any of which is optionally substituted with C₁-C₄alkyl, halo, C₁-C₄haloalkyl, C₁-C₄alkoxy or C₃-C₆cycloalkylC₀-C₁alkylene.
 4. A compound according to claim 3, wherein the heterocyclic ring is pyrrazol-1-yl, optionally substituted with C₁-C₄alkyl, halo, C₁-C₄haloalkyl, C₁-C₄alkoxy or cyclopropyl
 5. A compound according to claim 1, wherein R^(2a) and R^(2b) are both F.
 6. A compound according to claim 1, wherein R^(2a) is chloro, fluoro, trifluoromethyl or methoxy and R^(2b) is H.
 7. A compound according to claim 1, wherein R³ is neopentyl, cyclobutylmethyl, 1-methylcyclobutylmethyl or 1-methylcyclopentylmethyl, any of which is optionally substituted with one or two F or OMe.
 8. A compound according to claim 7, wherein R³ is 1-fluorocyclobutylmethyl.
 9. A compound according to claim 1, wherein R⁴ is morpholinyl, piperidinyl, piperazinyl, cyclopentyl, cyclohexyl or pyridinyl, any of which is optionally substituted with halo, hydroxy, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄-alkoxy, C₁-C₄haloalkoxy, amino, C₁-C₄alkylamino, di(C₁-C₄-alkyl)amino or NRkS(═O)mRq; where Rk is H or C₁-C₄alkyl; Rq is C₁-C₄alkyl, Het or Carbocyclyl, any of which is optionally substituted with C₁-C₄alkyl, halo, C₁-C₄haloalkyl, C₁-C₄alkoxy; and m is 0, 1 or
 2. 10. A compound according to claim 9 wherein R⁴ is morpholin-4-yl.
 11. A compound according to claim 9, wherein R⁴ is piperazin-1-yl or piperidin-1-yl, either of which is substituted at the 4 position or piperidin-4-yl substituted at the 1 position; in each case wherein the substituent is selected from —NHS(═O)₂Carbocyclyl or NHS(═O))Het, wherein the carbocyclyl or Het is optionally substituted with halo, C₁-C₄alkyl, C₁-C₄haloalkyl or C₁-C₄alkyoxy.
 12. A compound according to claim 9, wherein R⁴ is cyclohexyl or piperazin-1-yl substituted at the 4 position with halo, amino or hydroxy.
 13. A compound according to claim 1, wherein R⁴ is substituted phenyl.
 14. A compound according to claim 13, wherein the phenyl is substituted with 1-3 substituents independently selected from halo, hydroxy, C₁-C₄alkyl, C₁-C₄haloalkyl, cyano, C₁-C₄alkylC(═O)NH— or C₁-C₄alkoxy.
 15. A compound according to claim 14, wherein the phenyl is substituted with m-fluoro, p-fluoro, p-hydroxy, p-hydroxy-m-chloro, p-hydroxy-m-fluoro, p-hydroxy-m-methoxy, p-hydroxy-m-methyl, bis-p-chloro-p-hydroxy, m-cyano, p-acetamido or o-fluoro-p-hydroxy.
 16. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable vehicle therefor.
 17. Use of a compound as defined in claim 1 for the prophylaxis or treatement of a disorder characterised by inappropriate expression or activation of cathepsin S.
 18. Use according to claim 17, wherein the disorder is selected from a) Psoriasis; b) Autoimmune indications, including idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis (RA), multiple schlerosis (MS), myasthenia gravis (MG), Sjögrens syndrome, Grave's disease and systemic lupus erythematosis (SLE); or c) Non-autoimmune indications including allergic rhinitis, asthma, artherosclerosis, chronic obstructive pulmonary disease (COPD) and chronic pain.
 19. A method for the prophylaxis or treatment of a disorder characterised by inappropriate expression or activation of cathepsin S, the method comprising the administration of an effective amount of a compound as defined in claim 1 to a human or animal afflicted with or at risk of the disorder.
 20. A method according to claim 19, wherein the disorder is a) Psoriasis; b) An autoimmune indication selected from the group consisting of idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis (RA), multiple schlerosis (MS), myasthenia gravis (MG), Sjogrens syndrome, Grave's disease and systemic lupus erythematosis (SLE); or c) A non-automimmune indication selected from the group consisting of allergic rhinitis, asthma, artherosclerosis, chronic obstructive pulmonary disease (COPD) and chronic pain.
 21. A compound of the formula II

R^(2a) and R^(2b) are independently selected from H, halo, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxy; PG is H or a conventional N-protecting group; PG* is H or a conventional hydroxy protecting group. 9 SWG/eaw 